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125-454: Doxorubicin , sold under the brand name Adriamycin among others, is a chemotherapy medication used to treat cancer . This includes breast cancer , bladder cancer , Kaposi's sarcoma , lymphoma , and acute lymphocytic leukemia . It is often used together with other chemotherapy agents . Doxorubicin is given by injection into a vein . Common side effects include hair loss , bone marrow suppression , vomiting , rash, and inflammation of

250-480: A glycopeptide isolated from Streptomyces verticillus , also intercalates DNA, but produces free radicals that damage DNA. This occurs when bleomycin binds to a metal ion , becomes chemically reduced and reacts with oxygen . Mitomycin is a cytotoxic antibiotic with the ability to alkylate DNA. Most chemotherapy is delivered intravenously , although a number of agents can be administered orally (e.g., melphalan , busulfan , capecitabine ). According to

375-459: A nucleobase , a sugar and a phosphate group . The nucleobases are divided into purines ( guanine and adenine ) and pyrimidines ( cytosine , thymine and uracil ). Anti-metabolites resemble either nucleobases or nucleosides (a nucleotide without the phosphate group), but have altered chemical groups . These drugs exert their effect by either blocking the enzymes required for DNA synthesis or becoming incorporated into DNA or RNA. By inhibiting

500-512: A 50% mortality rate. There is no effective treatment against established cardiomyopathy caused by the drug as of 2010. The drug dexrazoxane , which is an iron chelator may be used to decrease the risk of doxorubicin's cardiotoxicity in certain cases. Another common and potentially fatal complication of doxorubicin is typhlitis , an acute life-threatening inflammation of the bowel. Additionally, some people may develop palmar plantar erythrodysesthesia (PPE), characterized by skin eruptions on

625-414: A certain dose, the effect plateaus and proportionally no more cell death occurs with increased doses. Subtypes of the anti-metabolites are the anti-folates , fluoropyrimidines, deoxynucleoside analogues and thiopurines . The anti-folates include methotrexate and pemetrexed . Methotrexate inhibits dihydrofolate reductase (DHFR), an enzyme that regenerates tetrahydrofolate from dihydrofolate . When

750-449: A common polymorphism involves the substitution of an arginine for a proline at codon position 72 of exon 4. Many studies have investigated a genetic link between this variation and cancer susceptibility; however, the results have been controversial. For instance, a meta-analysis from 2009 failed to show a link for cervical cancer. A 2011 study found that the TP53 proline mutation did have

875-460: A compound similar in structure to doxorubicin was found to inhibit plasmepsin II, an enzyme unique to the malarial parasite Plasmodium falciparum . The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth. Doxorubicin is also known to be fluorescent. This has often been used to characterize doxorubicin concentrations, and has opened

1000-406: A family history of cancer. Another 2011 study found that the p53 homozygous (Pro/Pro) genotype was associated with a significantly increased risk for renal cell carcinoma. p53 plays a role in regulation or progression through the cell cycle, apoptosis , and genomic stability by means of several mechanisms: WAF1/CIP1 encodes for p21 and hundreds of other down-stream genes. p21 (WAF1) binds to

1125-444: A high index of suspicion and the use of CT scanning, nonoperative treatment for uncomplicated cases, and sometimes elective right hemicolectomy to prevent recurrence. Nausea , vomiting , anorexia , diarrhea , abdominal cramps, and constipation are common side-effects of chemotherapeutic medications that kill fast-dividing cells. Malnutrition and dehydration can result when the recipient does not eat or drink enough, or when

1250-501: A higher therapeutic index , yet the cardiotoxicity remained. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines . Subsequent research has led to many other anthracycline antibiotics, or analogs, and there are now over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute (NCI). In 2016 GPX-150

1375-546: A large extent, chemotherapy can be thought of as a way to damage or stress cells, which may then lead to cell death if apoptosis is initiated. Many of the side effects of chemotherapy can be traced to damage to normal cells that divide rapidly and are thus sensitive to anti-mitotic drugs: cells in the bone marrow , digestive tract and hair follicles . This results in the most common side-effects of chemotherapy: myelosuppression (decreased production of blood cells, hence that also immunosuppression ), mucositis (inflammation of

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1500-626: A large number of phosphorylation sites and can be considered as the primary target for protein kinases transducing stress signals. The protein kinases that are known to target this transcriptional activation domain of p53 can be roughly divided into two groups. A first group of protein kinases belongs to the MAPK family (JNK1-3, ERK1-2, p38 MAPK), which is known to respond to several types of stress, such as membrane damage, oxidative stress, osmotic shock, heat shock, etc. A second group of protein kinases ( ATR , ATM , CHK1 and CHK2 , DNA-PK , CAK, TP53RK )

1625-479: A longer G1. This typically leads to abolition of S-phase entry, which stops the cell cycle in G1, leading to differentiation. Work in mouse embryonic stem cells has recently shown however that the expression of P53 does not necessarily lead to differentiation. p53 also activates miR-34a and miR-145 , which then repress the hESCs pluripotency factors, further instigating differentiation. In adult stem cells, p53 regulation

1750-479: A much greater efficiency than normal cells. Papers suggest that the lack of cell cycle arrest and apoptosis gives more cells the chance to be reprogrammed. Decreased levels of p53 were also shown to be a crucial aspect of blastema formation in the legs of salamanders. p53 regulation is very important in acting as a barrier between stem cells and a differentiated stem cell state, as well as a barrier between stem cells being functional and being cancerous. Apart from

1875-417: A number of strategies in the administration of chemotherapeutic drugs used today. Chemotherapy may be given with a curative intent or it may aim to prolong life or to palliate symptoms . All chemotherapy regimens require that the recipient be capable of undergoing the treatment. Performance status is often used as a measure to determine whether a person can receive chemotherapy, or whether dose reduction

2000-506: A pre-Roman tribe that occupied the area of Italy where the compound was isolated, with the French word for ruby , rubis , describing the color. Clinical trials began in the 1960s, and the drug was successful in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could lead to fatal cardiac toxicity. Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in

2125-767: A preventative and treatment effect of diarrhoea related to chemotherapy alone and with radiotherapy. However, a high index of suspicion is appropriate, since diarrhoea and bloating are also symptoms of typhlitis , a very serious and potentially life-threatening medical emergency that requires immediate treatment. Anemia can be a combined outcome caused by myelosuppressive chemotherapy, and possible cancer-related causes such as bleeding , blood cell destruction ( hemolysis ), hereditary disease, kidney dysfunction, nutritional deficiencies or anemia of chronic disease . Treatments to mitigate anemia include hormones to boost blood production ( erythropoietin ), iron supplements , and blood transfusions . Myelosuppressive therapy can cause

2250-418: A profound effect on pancreatic cancer risk among males. A study of Arab women found that proline homozygosity at TP53 codon 72 is associated with a decreased risk for breast cancer. One study suggested that TP53 codon 72 polymorphisms, MDM2 SNP309 , and A2164G may collectively be associated with non-oropharyngeal cancer susceptibility and that MDM2 SNP309 in combination with TP53 codon 72 may accelerate

2375-601: A recent (2016) systematic review, oral therapies present additional challenges for patients and care teams to maintain and support adherence to treatment plans. There are many intravenous methods of drug delivery, known as vascular access devices. These include the winged infusion device , peripheral venous catheter , midline catheter, peripherally inserted central catheter (PICC), central venous catheter and implantable port . The devices have different applications regarding duration of chemotherapy treatment, method of delivery and types of chemotherapeutic agent. Depending on

2500-401: A state of assembly and disassembly. Vinca alkaloids and taxanes are the two main groups of anti-microtubule agents, and although both of these groups of drugs cause microtubule dysfunction, their mechanisms of action are completely opposite: Vinca alkaloids prevent the assembly of microtubules, whereas taxanes prevent their disassembly. By doing so, they can induce mitotic catastrophe in

2625-1159: A tendency to bleed easily, leading to anemia. Medications that kill rapidly dividing cells or blood cells can reduce the number of platelets in the blood, which can result in bruises and bleeding . Extremely low platelet counts may be temporarily boosted through platelet transfusions and new drugs to increase platelet counts during chemotherapy are being developed. Sometimes, chemotherapy treatments are postponed to allow platelet counts to recover. P53 7157 22059 ENSG00000141510 ENSMUSG00000059552 P04637 P02340 NM_001126115 NM_001126116 NM_001126117 NM_001126118 NM_001276695 NM_001276696 NM_001276697 NM_001276698 NM_001276699 NM_001276760 NM_001127233 NM_011640 NP_001119588 NP_001119589 NP_001119590 NP_001263624 NP_001263625 NP_001263626 NP_001263627 NP_001263628 NP_001263689 NP_001263690 NP_001120705 NP_035770 p53 , also known as Tumor protein P53 , cellular tumor antigen p53 ( UniProt name), or transformation-related protein 53 (TRP53)

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2750-894: Is indicated to treat breast cancer, ovarian cancer, and AIDS-related Kaposi's sarcoma. It is indicated to treat multiple myeloma in combination with bortezomib . Doxorubicin hydrochloride (as Myocet liposomal) is indicated to treat breast cancer in combination with cyclophosphamide . Doxorubicin is commonly used to treat some leukemias and lymphomas , as well as cancers of the bladder , breast , stomach , lung , ovaries , thyroid , soft tissue sarcoma as well as aggressive fibromatosis (desmoid tumor), multiple myeloma , and others. Commonly used doxorubicin-containing regimens are AC (Adriamycin, cyclophosphamide ), TAC ( taxotere , AC), ABVD (Adriamycin, bleomycin , vinblastine , dacarbazine ), BEACOPP , CHOP (cyclophosphamide, hydroxydaunorubicin, vincristine , prednisone ) and FAC ( 5-fluorouracil , adriamycin, cyclophosphamide). Its activity

2875-484: Is systemic therapy for cancer: they are introduced into the blood stream (the system) and therefore can treat cancer anywhere in the body. Systemic therapy is often used with other, local therapy (treatments that work only where they are applied), such as radiation , surgery , and hyperthermia . Traditional chemotherapeutic agents are cytotoxic by means of interfering with cell division (mitosis) but cancer cells vary widely in their susceptibility to these agents. To

3000-560: Is Accord Healthcare S.L.U. Zolsketil pegylated liposomal is a hybrid medicine of Adriamycin. It contains the same active substance as Adriamycin, but is available in a pegylated liposomal formulation. Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022. On 21 July 2022, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for

3125-437: Is a pegylated (polyethylene glycol coated) liposome -encapsulated form of doxorubicin, developed to treat Kaposi's sarcoma . The polyethylene glycol coating results in preferential concentration of doxorubicin in the skin. However, this also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome. Following administration of this form of doxorubicin, small amounts of

3250-479: Is a "life-threatening gastrointestinal complication of chemotherapy." Typhlitis is an intestinal infection which may manifest itself through symptoms including nausea , vomiting , diarrhea , a distended abdomen , fever , chills , or abdominal pain and tenderness. Typhlitis is a medical emergency . It has a very poor prognosis and is often fatal unless promptly recognized and aggressively treated. Successful treatment hinges on early diagnosis provided by

3375-453: Is a better binding partner to Mdm2 than p53 in unstressed cells. USP10 , however, has been shown to be located in the cytoplasm in unstressed cells and deubiquitinates cytoplasmic p53, reversing Mdm2 ubiquitination. Following DNA damage, USP10 translocates to the nucleus and contributes to p53 stability. Also USP10 does not interact with Mdm2. Phosphorylation of the N-terminal end of p53 by

3500-1054: Is a nucleobase analogue that is metabolised in cells to form at least two active products; 5-fluourouridine monophosphate (FUMP) and 5-fluoro-2'-deoxyuridine 5'-phosphate (fdUMP). FUMP becomes incorporated into RNA and fdUMP inhibits the enzyme thymidylate synthase; both of which lead to cell death. Capecitabine is a prodrug of 5-fluorouracil that is broken down in cells to produce the active drug. The deoxynucleoside analogues include cytarabine , gemcitabine , decitabine , azacitidine , fludarabine , nelarabine , cladribine , clofarabine , and pentostatin . The thiopurines include thioguanine and mercaptopurine . Anti-microtubule agents are plant -derived chemicals that block cell division by preventing microtubule function. Microtubules are an important cellular structure composed of two proteins, α-tubulin and β-tubulin . They are hollow, rod-shaped structures that are required for cell division, among other cellular functions. Microtubules are dynamic structures, which means that they are permanently in

3625-442: Is a regulatory protein that is often mutated in human cancers. The p53 proteins (originally thought to be, and often spoken of as, a single protein) are crucial in vertebrates , where they prevent cancer formation. As such, p53 has been described as "the guardian of the genome " because of its role in conserving stability by preventing genome mutation. Hence TP53 is classified as a tumor suppressor gene . The TP53 gene

3750-462: Is also available in liposome -encapsulated forms as Doxil ( pegylated form), Myocet (nonpegylated form), and Caelyx, which are also given by intravenous injection. The FDA approved the first generic version of Doxil, made by Sun, in February 2013. Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt -positive lymphomas in mice. Further,

3875-563: Is an important factor in achieving better treatment outcomes. Similar results were found in a study involving people with colorectal cancer who have been treated with the popular FOLFOX regimen. The incidence of serious diarrhea was reduced from 12% in the BSA-dosed group of patients to 1.7% in the dose-adjusted group, and the incidence of severe mucositis was reduced from 15% to 0.8%. The FOLFOX study also demonstrated an improvement in treatment outcomes. Positive response increased from 46% in

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4000-495: Is an independent prognostic predictor of survival in various cancer types. Alkylating agents are the oldest group of chemotherapeutics in use today. Originally derived from mustard gas used in World War I , there are now many types of alkylating agents in use. They are so named because of their ability to alkylate many molecules, including proteins , RNA and DNA . This ability to bind covalently to DNA via their alkyl group

4125-782: Is called medical oncology . The term chemotherapy now means the non-specific use of intracellular poisons to inhibit mitosis (cell division) or to induce DNA damage (so that DNA repair can augment chemotherapy). This meaning excludes the more-selective agents that block extracellular signals ( signal transduction ). Therapies with specific molecular or genetic targets, which inhibit growth-promoting signals from classic endocrine hormones (primarily estrogens for breast cancer and androgens for prostate cancer), are now called hormonal therapies . Other inhibitions of growth-signals, such as those associated with receptor tyrosine kinases , are targeted therapy . The use of drugs (whether chemotherapy, hormonal therapy, or targeted therapy)

4250-654: Is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550 mg/m, 18% when the dose is 551–600 mg/m and 36% when the dose exceeds 600 mg/m. There are several ways in which doxorubicin is believed to cause cardiomyopathy, including oxidative stress due to iron accumulation, downregulation of genes for contractile proteins, and p53 -mediated apoptosis . Doxorubicin-induced cardiomyopathy typically results in dilated cardiomyopathy, with all four cardiac chambers being enlarged. This results in both systolic and diastolic dysfunction. Eventually, heart failure can result, which carries

4375-434: Is implicated in the genome integrity checkpoint, a molecular cascade that detects and responds to several forms of DNA damage caused by genotoxic stress. Oncogenes also stimulate p53 activation, mediated by the protein p14ARF . In unstressed cells, p53 levels are kept low through a continuous degradation of p53. A protein called Mdm2 (also called HDM2 in humans), binds to p53, preventing its action and transports it from

4500-519: Is important for maintenance of stemness in adult stem cell niches . Mechanical signals such as hypoxia affect levels of p53 in these niche cells through the hypoxia inducible factors , HIF-1α and HIF-2α. While HIF-1α stabilizes p53, HIF-2α suppresses it. Suppression of p53 plays important roles in cancer stem cell phenotype, induced pluripotent stem cells and other stem cell roles and behaviors, such as blastema formation. Cells with decreased levels of p53 have been shown to reprogram into stem cells with

4625-459: Is inhibited by certain antioxidant plant extracts, for example Tragia volubilis aqueous extract. Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum-based chemotherapy , or for the treatment of AIDS -related Kaposi's sarcoma . The most dangerous side effect of doxorubicin is dilated cardiomyopathy , leading to congestive heart failure . The rate of cardiomyopathy

4750-485: Is known that single missense mutations can have a large spectrum from rather mild to very severe functional effects. The large spectrum of cancer phenotypes due to mutations in the TP53 gene is also supported by the fact that different isoforms of p53 proteins have different cellular mechanisms for prevention against cancer. Mutations in TP53 can give rise to different isoforms, preventing their overall functionality in different cellular mechanisms and thereby extending

4875-433: Is maintained at low inactive levels. This is because activation of p53 leads to rapid differentiation of hESCs. Studies have shown that knocking out p53 delays differentiation and that adding p53 causes spontaneous differentiation, showing how p53 promotes differentiation of hESCs and plays a key role in cell cycle as a differentiation regulator. When p53 becomes stabilized and activated in hESCs, it increases p21 to establish

5000-423: Is marked by two major events. First, the half-life of the p53 protein is increased drastically, leading to a quick accumulation of p53 in stressed cells. Second, a conformational change forces p53 to be activated as a transcription regulator in these cells. The critical event leading to the activation of p53 is the phosphorylation of its N-terminal domain. The N-terminal transcriptional activation domain contains

5125-531: Is obtained from the Chinese ornamental tree Camptotheca acuminata . Drugs that target topoisomerase II can be divided into two groups. The topoisomerase II poisons cause increased levels enzymes bound to DNA. This prevents DNA replication and transcription, causes DNA strand breaks, and leads to programmed cell death ( apoptosis ). These agents include etoposide , doxorubicin , mitoxantrone and teniposide . The second group, catalytic inhibitors, are drugs that block

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5250-668: Is required. Because only a fraction of the cells in a tumor die with each treatment ( fractional kill ), repeated doses must be administered to continue to reduce the size of the tumor. Current chemotherapy regimens apply drug treatment in cycles, with the frequency and duration of treatments limited by toxicity. The effectiveness of chemotherapy depends on the type of cancer and the stage. The overall effectiveness ranges from being curative for some cancers, such as some leukemias , to being ineffective, such as in some brain tumors , to being needless in others, like most non-melanoma skin cancers . Dosage of chemotherapy can be difficult: If

5375-403: Is shown to lead to increased CXCR5 chemokine receptor gene expression and activated cell migration in response to chemokine CXCL13 . One study found that p53 and Myc proteins were key to the survival of Chronic Myeloid Leukaemia (CML) cells. Targeting p53 and Myc proteins with drugs gave positive results on mice with CML. Most p53 mutations are detected by DNA sequencing. However, it

5500-490: Is similar to that of vinca alkaloids in that they bind to tubulin, inhibiting microtubule formation. Podophyllotoxin is used to produce two other drugs with different mechanisms of action: etoposide and teniposide . Topoisomerase inhibitors are drugs that affect the activity of two enzymes: topoisomerase I and topoisomerase II . When the DNA double-strand helix is unwound, during DNA replication or transcription , for example,

5625-426: Is that they interrupt cell division . The most important subgroup is the anthracyclines and the bleomycins ; other prominent examples include mitomycin C and actinomycin . Among the anthracyclines, doxorubicin and daunorubicin were the first, and were obtained from the bacterium Streptomyces peucetius . Derivatives of these compounds include epirubicin and idarubicin . Other clinically used drugs in

5750-406: Is the most frequently mutated gene (>50%) in human cancer, indicating that the TP53 gene plays a crucial role in preventing cancer formation. TP53 gene encodes proteins that bind to DNA and regulate gene expression to prevent mutations of the genome. In addition to the full-length protein, the human TP53 gene encodes at least 12 protein isoforms . In humans, the TP53 gene is located on

5875-455: Is the primary cause for their anti-cancer effects. DNA is made of two strands and the molecules may either bind twice to one strand of DNA (intrastrand crosslink) or may bind once to both strands (interstrand crosslink). If the cell tries to replicate crosslinked DNA during cell division , or tries to repair it, the DNA strands can break. This leads to a form of programmed cell death called apoptosis . Alkylating agents will work at any point in

6000-474: Is the type of cancer treatment that uses one or more anti-cancer drugs ( chemotherapeutic agents or alkylating agents ) in a standard regimen . Chemotherapy may be given with a curative intent (which almost always involves combinations of drugs), or it may aim only to prolong life or to reduce symptoms ( palliative chemotherapy). Chemotherapy is one of the major categories of the medical discipline specifically devoted to pharmacotherapy for cancer , which

6125-582: The G1 - S / CDK ( CDK4 / CDK6 , CDK2 , and CDK1 ) complexes (molecules important for the G1/S transition in the cell cycle) inhibiting their activity. When p21(WAF1) is complexed with CDK2, the cell cannot continue to the next stage of cell division. A mutant p53 will no longer bind DNA in an effective way, and, as a consequence, the p21 protein will not be available to act as the "stop signal" for cell division. Studies of human embryonic stem cells (hESCs) commonly describe

6250-828: The PICC line . These have a lower infection risk, are much less prone to phlebitis or extravasation , and eliminate the need for repeated insertion of peripheral cannulae. Isolated limb perfusion (often used in melanoma ), or isolated infusion of chemotherapy into the liver or the lung have been used to treat some tumors. The main purpose of these approaches is to deliver a very high dose of chemotherapy to tumor sites without causing overwhelming systemic damage. These approaches can help control solitary or limited metastases, but they are by definition not systemic, and, therefore, do not treat distributed metastases or micrometastases . Topical chemotherapies, such as 5-fluorouracil , are used to treat some cases of non-melanoma skin cancer . If

6375-399: The amino , carboxyl , sulfhydryl , and phosphate groups in biologically important molecules. Non-classical alkylating agents include procarbazine and hexamethylmelamine. Anti-metabolites are a group of molecules that impede DNA and RNA synthesis. Many of them have a similar structure to the building blocks of DNA and RNA. The building blocks are nucleotides ; a molecule comprising

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6500-470: The genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR. By 1999, they produced recombinant dox A, a cytochrome P450 oxidase , and found that it catalyzes multiple steps in DXR biosynthesis , including steps leading to daunorubicin. This

6625-521: The immune system , often by paralysing the bone marrow and leading to a decrease of white blood cells , red blood cells , and platelets . Anemia and thrombocytopenia may require blood transfusion . Neutropenia (a decrease of the neutrophil granulocyte count below 0.5 x 10 / litre ) can be improved with synthetic G-CSF ( granulocyte -colony-stimulating factor, e.g., filgrastim , lenograstim , efbemalenograstim alfa ). In very severe myelosuppression , which occurs in some regimens, almost all

6750-438: The nucleus to the cytosol . Mdm2 also acts as an ubiquitin ligase and covalently attaches ubiquitin to p53 and thus marks p53 for degradation by the proteasome . However, ubiquitylation of p53 is reversible. On activation of p53, Mdm2 is also activated, setting up a feedback loop . p53 levels can show oscillations (or repeated pulses) in response to certain stresses, and these pulses can be important in determining whether

6875-468: The 5-FU clinical study cited above, people whose dose was adjusted to achieve a pre-determined target exposure realized an 84% improvement in treatment response rate and a six-month improvement in overall survival (OS) compared with those dosed by BSA. In the same study, investigators compared the incidence of common 5-FU-associated grade 3/4 toxicities between the dose-adjusted people and people dosed per BSA. The incidence of debilitating grades of diarrhea

7000-597: The BSA-dosed group to 70% in the dose-adjusted group. Median progression free survival (PFS) and overall survival (OS) both improved by six months in the dose adjusted group. One approach that can help clinicians individualize chemotherapy dosing is to measure the drug levels in blood plasma over time and adjust dose according to a formula or algorithm to achieve optimal exposure. With an established target exposure for optimized treatment effectiveness with minimized toxicities, dosing can be personalized to achieve target exposure and optimal results for each person. Such an algorithm

7125-467: The DNA chain for replication, preventing the DNA double helix from being released and thereby stopping the process of replication . It may also increase quinone type free radical production, hence contributing to its cytotoxicity. The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to

7250-544: The HPV protein E7, allows for repeated cell division manifested clinically as warts . Certain HPV types, in particular types 16 and 18, can also lead to progression from a benign wart to low or high-grade cervical dysplasia , which are reversible forms of precancerous lesions. Persistent infection of the cervix over the years can cause irreversible changes leading to carcinoma in situ and eventually invasive cervical cancer. This results from

7375-434: The ability of p53 to respond to stress. Recent research has shown that HAUSP is mainly localized in the nucleus, though a fraction of it can be found in the cytoplasm and mitochondria. Overexpression of HAUSP results in p53 stabilization. However, depletion of HAUSP does not result in a decrease in p53 levels but rather increases p53 levels due to the fact that HAUSP binds and deubiquitinates Mdm2. It has been shown that HAUSP

7500-631: The above-mentioned protein kinases disrupts Mdm2-binding. Other proteins, such as Pin1, are then recruited to p53 and induce a conformational change in p53, which prevents Mdm2-binding even more. Phosphorylation also allows for binding of transcriptional coactivators, like p300 and PCAF , which then acetylate the C-terminal end of p53, exposing the DNA binding domain of p53, allowing it to activate or repress specific genes. Deacetylase enzymes, such as Sirt1 and Sirt7 , can deacetylate p53, leading to an inhibition of apoptosis. Some oncogenes can also stimulate

7625-410: The activity of topoisomerase II, and therefore prevent DNA synthesis and translation because the DNA cannot unwind properly. This group includes novobiocin , merbarone, and aclarubicin , which also have other significant mechanisms of action. The cytotoxic antibiotics are a varied group of drugs that have various mechanisms of action. The common theme that they share in their chemotherapy indication

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7750-560: The adjacent unopened DNA winds tighter (supercoils), like opening the middle of a twisted rope. The stress caused by this effect is in part aided by the topoisomerase enzymes. They produce single- or double-strand breaks into DNA, reducing the tension in the DNA strand. This allows the normal unwinding of DNA to occur during replication or transcription. Inhibition of topoisomerase I or II interferes with both of these processes. Two topoisomerase I inhibitors, irinotecan and topotecan , are semi-synthetically derived from camptothecin , which

7875-405: The anthracycline group are pirarubicin , aclarubicin , and mitoxantrone . The mechanisms of anthracyclines include DNA intercalation (molecules insert between the two strands of DNA), generation of highly reactive free radicals that damage intercellular molecules and topoisomerase inhibition. Actinomycin is a complex molecule that intercalates DNA and prevents RNA synthesis . Bleomycin,

8000-633: The assembly of tubulin into microtubules. The original vinca alkaloids are natural products that include vincristine and vinblastine . Following the success of these drugs, semi-synthetic vinca alkaloids were produced: vinorelbine (used in the treatment of non-small-cell lung cancer ), vindesine , and vinflunine . These drugs are cell cycle -specific. They bind to the tubulin molecules in S-phase and prevent proper microtubule formation required for M-phase . Taxanes are natural and semi-synthetic drugs. The first drug of their class, paclitaxel ,

8125-645: The bone marrow stem cells (cells that produce white and red blood cells ) are destroyed, meaning allogenic or autologous bone marrow cell transplants are necessary. (In autologous BMTs, cells are removed from the person before the treatment, multiplied and then re-injected afterward; in allogenic BMTs, the source is a donor.) However, some people still develop diseases because of this interference with bone marrow. Although people receiving chemotherapy are encouraged to wash their hands, avoid sick people, and take other infection-reducing steps, about 85% of infections are due to naturally occurring microorganisms in

8250-469: The cancer cells. Following this, cell cycle arrest occurs, which induces programmed cell death ( apoptosis ). These drugs can also affect blood vessel growth , an essential process that tumours utilise in order to grow and metastasise. Vinca alkaloids are derived from the Madagascar periwinkle , Catharanthus roseus , formerly known as Vinca rosea . They bind to specific sites on tubulin, inhibiting

8375-589: The cancer has central nervous system involvement, or with meningeal disease, intrathecal chemotherapy may be administered. Chemotherapeutic techniques have a range of side effects that depend on the type of medications used. The most common medications affect mainly the fast-dividing cells of the body, such as blood cells and the cells lining the mouth, stomach, and intestines. Chemotherapy-related toxicities can occur acutely after administration, within hours or days, or chronically, from weeks to years. Virtually all chemotherapeutic regimens can cause depression of

8500-486: The cancer phenotype from mild to severe. Recent studies show that p53 isoforms are differentially expressed in different human tissues, and the loss-of-function or gain-of-function mutations within the isoforms can cause tissue-specific cancer or provide cancer stem cell potential in different tissues. TP53 mutation also hits energy metabolism and increases glycolysis in breast cancer cells. The dynamics of p53 proteins, along with its antagonist Mdm2 , indicate that

8625-415: The cell cycle and inhibits their kinase activity, thereby causing cell cycle arrest to allow repair to take place. p21 can also mediate growth arrest associated with differentiation and a more permanent growth arrest associated with cellular senescence. The p21 gene contains several p53 response elements that mediate direct binding of the p53 protein, resulting in transcriptional activation of the gene encoding

8750-933: The cell cycle and thus are known as cell cycle-independent drugs. For this reason, the effect on the cell is dose dependent; the fraction of cells that die is directly proportional to the dose of drug. The subtypes of alkylating agents are the nitrogen mustards , nitrosoureas , tetrazines , aziridines , cisplatins and derivatives, and non-classical alkylating agents. Nitrogen mustards include mechlorethamine , cyclophosphamide , melphalan , chlorambucil , ifosfamide and busulfan . Nitrosoureas include N-Nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU) and semustine (MeCCNU), fotemustine and streptozotocin . Tetrazines include dacarbazine , mitozolomide and temozolomide . Aziridines include thiotepa , mytomycin and diaziquone (AZQ). Cisplatin and derivatives include cisplatin , carboplatin and oxaliplatin . They impair cell function by forming covalent bonds with

8875-469: The cells survive the stress, or die. MI-63 binds to MDM2, reactivating p53 in situations where p53's function has become inhibited. A ubiquitin specific protease, USP7 (or HAUSP ), can cleave ubiquitin off p53, thereby protecting it from proteasome-dependent degradation via the ubiquitin ligase pathway . This is one means by which p53 is stabilized in response to oncogenic insults. USP42 has also been shown to deubiquitinate p53 and may be required for

9000-418: The cellular and molecular effects above, p53 has a tissue-level anticancer effect that works by inhibiting angiogenesis . As tumors grow they need to recruit new blood vessels to supply them, and p53 inhibits that by (i) interfering with regulators of tumor hypoxia that also affect angiogenesis, such as HIF1 and HIF2, (ii) inhibiting the production of angiogenic promoting factors, and (iii) directly increasing

9125-452: The combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as congestive heart failure (CHF). Published phase II study results have shown that Myocet, trastuzumab, and paclitaxel can safely be used concurrently without the cardiac risk, as measured by reduction in LVEF function, while still achieving superior tumor response. This finding is the basis for

9250-448: The development of non-oropharyngeal cancer in women. A 2011 study found that TP53 codon 72 polymorphism was associated with an increased risk of lung cancer. Meta-analyses from 2011 found no significant associations between TP53 codon 72 polymorphisms and both colorectal cancer risk and endometrial cancer risk. A 2011 study of a Brazilian birth cohort found an association between the non-mutant arginine TP53 and individuals without

9375-452: The dose is too low, it will be ineffective against the tumor, whereas, at excessive doses, the toxicity ( side-effects ) will be intolerable to the person receiving it. The standard method of determining chemotherapy dosage is based on calculated body surface area (BSA). The BSA is usually calculated with a mathematical formula or a nomogram , using the recipient's weight and height, rather than by direct measurement of body area. This formula

9500-430: The drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50 mg/m dosing every four weeks, half of people developed hand-foot syndrome. The rate of this side effect limits the dose of this formulation that can be given as compared with plain doxorubicin in

9625-404: The effects of HPV genes, particularly those encoding E6 and E7, which are the two viral oncoproteins that are preferentially retained and expressed in cervical cancers by integration of the viral DNA into the host genome. The p53 protein is continually produced and degraded in cells of healthy people, resulting in damped oscillation (see a stochastic model of this process in ). The degradation of

9750-622: The enzyme is inhibited by methotrexate, the cellular levels of folate coenzymes diminish. These are required for thymidylate and purine production, which are both essential for DNA synthesis and cell division. Pemetrexed is another anti-metabolite that affects purine and pyrimidine production, and therefore also inhibits DNA synthesis. It primarily inhibits the enzyme thymidylate synthase , but also has effects on DHFR, aminoimidazole carboxamide ribonucleotide formyltransferase and glycinamide ribonucleotide formyltransferase . The fluoropyrimidines include fluorouracil and capecitabine . Fluorouracil

9875-443: The enzymes involved in DNA synthesis, they prevent mitosis because the DNA cannot duplicate itself. Also, after misincorporation of the molecules into DNA, DNA damage can occur and programmed cell death ( apoptosis ) is induced. Unlike alkylating agents, anti-metabolites are cell cycle dependent. This means that they only work during a specific part of the cell cycle, in this case S-phase (the DNA synthesis phase). For this reason, at

10000-582: The formula only takes into account the individual's weight and height. Drug absorption and clearance are influenced by multiple factors, including age, sex, metabolism, disease state, organ function, drug-to-drug interactions, genetics, and obesity, which have major impacts on the actual concentration of the drug in the person's bloodstream. As a result, there is high variability in the systemic chemotherapy drug concentration in people dosed by BSA, and this variability has been demonstrated to be more than ten-fold for many drugs. In other words, if two people receive

10125-573: The function of DNA . Doxorubicin was approved for medical use in the United States in 1974. It is on the World Health Organization's List of Essential Medicines . Versions that are pegylated and in liposomes are also available; however, they are more expensive. Doxorubicin was originally made from the bacterium Streptomyces peucetius . In the EU doxorubicin pegylated liposomal (as Caelyx)

10250-419: The histone profile at key target genes and act in a gene-specific manner. If the TP53 gene is damaged, tumor suppression is severely compromised. People who inherit only one functional copy of the TP53 gene will most likely develop tumors in early adulthood, a disorder known as Li–Fraumeni syndrome . The TP53 gene can also be modified by mutagens ( chemicals , radiation , or viruses ), increasing

10375-536: The immune system is suppressed to a critically low level. In Japan , the government has approved the use of some medicinal mushrooms like Trametes versicolor , to counteract depression of the immune system in people undergoing chemotherapy. Trilaciclib is an inhibitor of cyclin-dependent kinase 4/6 approved for the prevention of myelosuppression caused by chemotherapy. The drug is given before chemotherapy to protect bone marrow function. Due to immune system suppression, neutropenic enterocolitis (typhlitis)

10500-518: The intercalation site, as evidenced by several crystal structures. By intercalation , doxorubicin can also induce histone eviction from transcriptionally active chromatin . As a result, the DNA damage response , epigenome and transcriptome are deregulated in doxorubicin-exposed cells. In the 1950s, an Italian research company, Farmitalia Research Laboratories, began an organized effort to find anticancer compounds from soil-based microbes. A soil sample

10625-563: The levels of p53, in units of concentration, oscillate as a function of time. This " damped " oscillation is both clinically documented and mathematically modelled . Mathematical models also indicate that the p53 concentration oscillates much faster once teratogens, such as double-stranded breaks (DSB) or UV radiation , are introduced to the system . This supports and models the current understanding of p53 dynamics, where DNA damage induces p53 activation (see p53 regulation for more information). Current models can also be useful for modelling

10750-617: The likelihood for uncontrolled cell division. More than 50 percent of human tumors contain a mutation or deletion of the TP53 gene. Loss of p53 creates genomic instability that most often results in an aneuploidy phenotype. Increasing the amount of p53 may seem a solution for treatment of tumors or prevention of their spreading. This, however, is not a usable method of treatment, since it can cause premature aging. Restoring endogenous normal p53 function holds some promise. Research has shown that this restoration can lead to regression of certain cancer cells without damaging other cells in

10875-417: The lining of the digestive tract), and alopecia (hair loss). Because of the effect on immune cells (especially lymphocytes), chemotherapy drugs often find use in a host of diseases that result from harmful overactivity of the immune system against self (so-called autoimmunity ). These include rheumatoid arthritis , systemic lupus erythematosus , multiple sclerosis , vasculitis and many others. There are

11000-531: The liposomal encapsulation of the doxorubicin limits the cardiotoxicity. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as trastuzumab . There is an FDA black box warning that trastuzumab cannot be used in concurrent combination with doxorubicin, only in sequential combination. Though concurrent combination of trastuzumab and doxorubicin in clinical studies found superior tumor response,

11125-450: The medicinal product Celdoxome pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma. The applicant for this medicinal product is YES Pharmaceutical Development Services GmbH. Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979. Celdoxome pegylated liposomal contains

11250-400: The mouth . Other serious side effects may include allergic reactions such as anaphylaxis , heart damage , tissue damage at the site of injection, radiation recall , and treatment-related leukemia . People often experience red discoloration of the urine for a few days. Doxorubicin is in the anthracycline and antitumor antibiotic family of medications. It works in part by interfering with

11375-464: The mutations in p53 isoforms and their effects on p53 oscillation, thereby promoting de novo tissue-specific pharmacological drug discovery . p53 was identified in 1979 by Lionel Crawford , David P. Lane , Arnold Levine , and Lloyd Old , working at Imperial Cancer Research Fund (UK) Princeton University /UMDNJ (Cancer Institute of New Jersey), and Memorial Sloan Kettering Cancer Center , respectively. It had been hypothesized to exist before as

11500-590: The nonfunctional p53-p21 axis of the G1/S checkpoint pathway with subsequent relevance for cell cycle regulation and the DNA damage response (DDR). Importantly, p21 mRNA is clearly present and upregulated after the DDR in hESCs, but p21 protein is not detectable. In this cell type, p53 activates numerous microRNAs (like miR-302a, miR-302b, miR-302c, and miR-302d) that directly inhibit the p21 expression in hESCs. The p21 protein binds directly to cyclin-CDK complexes that drive forward

11625-449: The ongoing phase III trial for FDA approval. Doxorubicin (DXR) is a 14- hydroxylated version of daunorubicin , the immediate precursor of DXR in its biosynthetic pathway. Daunorubicin is more abundantly found as a natural product because it is produced by a number of different wild type strains of Streptomyces . In contrast, only one known non- wild type species , Streptomyces peucetius subspecies cesius ATCC 27952,

11750-451: The p21 protein. The p53 and RB1 pathways are linked via p14ARF, raising the possibility that the pathways may regulate each other. p53 expression can be stimulated by UV light, which also causes DNA damage. In this case, p53 can initiate events leading to tanning . Levels of p53 play an important role in the maintenance of stem cells throughout development and the rest of human life. In human embryonic stem cells (hESCs)s, p53

11875-712: The p53 protein is associated with binding of MDM2. In a negative feedback loop, MDM2 itself is induced by the p53 protein. Mutant p53 proteins often fail to induce MDM2, causing p53 to accumulate at very high levels. Moreover, the mutant p53 protein itself can inhibit normal p53 protein levels. In some cases, single missense mutations in p53 have been shown to disrupt p53 stability and function. This image shows different patterns of p53 expression in endometrial cancers on chromogenic immunohistochemistry , whereof all except wild-type are variably termed abnormal/aberrant/mutation-type and are strongly predictive of an underlying TP53 mutation: Suppression of p53 in human breast cancer cells

12000-425: The palms of the hand or soles of the feet, swelling, pain, and erythema . Due to these side effects and its red color, doxorubicin has earned the nickname "red devil" or "red death." Chemotherapy can cause reactivation of hepatitis B , and doxorubicin-containing regimens are no exception. Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss of skin pigmentation . There

12125-412: The person vomits frequently, because of gastrointestinal damage. This can result in rapid weight loss, or occasionally in weight gain, if the person eats too much in an effort to allay nausea or heartburn. Weight gain can also be caused by some steroid medications. These side-effects can frequently be reduced or eliminated with antiemetic drugs. Low-certainty evidence also suggests that probiotics may have

12250-818: The person's own gastrointestinal tract (including oral cavity ) and skin. This may manifest as systemic infections, such as sepsis , or as localized outbreaks, such as Herpes simplex , shingles , or other members of the Herpesviridea . The risk of illness and death can be reduced by taking common antibiotics such as quinolones or trimethoprim/sulfamethoxazole before any fever or sign of infection appears. Quinolones show effective prophylaxis mainly with hematological cancer. However, in general, for every five people who are immunosuppressed following chemotherapy who take an antibiotic, one fever can be prevented; for every 34 who take an antibiotic, one death can be prevented. Sometimes, chemotherapy treatments are postponed because

12375-511: The person, the cancer, the stage of cancer, the type of chemotherapy, and the dosage, intravenous chemotherapy may be given on either an inpatient or an outpatient basis. For continuous, frequent or prolonged intravenous chemotherapy administration, various systems may be surgically inserted into the vasculature to maintain access. Commonly used systems are the Hickman line , the Port-a-Cath , and

12500-583: The possibility of using the molecule as a theranostic agent. However, there are significant limitations, as doxorubicin's fluorescence spectrum is known to depend on a variety of factors, including the pH of the environment, solvent dielectric constant and others. Doxorubicin fluorescence is quenched by binding to DNA, and shielded by micelle encapsulation. It is also known to self-quench at high concentrations. In contrast, histone binding amplifies fluorescence. Chemotherapy medication Chemotherapy (often abbreviated chemo , sometimes CTX and CTx )

12625-455: The process. The ways by which tumor regression occurs depends mainly on the tumor type. For example, restoration of endogenous p53 function in lymphomas may induce apoptosis , while cell growth may be reduced to normal levels. Thus, pharmacological reactivation of p53 presents itself as a viable cancer treatment option. The first commercial gene therapy, Gendicine , was approved in China in 2003 for

12750-407: The production of angiogenesis inhibitors, such as arresten . p53 by regulating Leukemia Inhibitory Factor has been shown to facilitate implantation in the mouse and possibly human reproduction. The immune response to infection also involves p53 and NF-κB . Checkpoint control of the cell cycle and of apoptosis by p53 is inhibited by some infections such as Mycoplasma bacteria, raising

12875-471: The release of photo-activated adriamycin with the aid of nanoporous optical antenna resulted in significant anti-cancer effect in MCF-7 breast cancer cells. In 2006, animal research coupling a murine monoclonal antibody with doxorubicin created an immunoconjugate that was able to eliminate HIV-1 infection in mice. There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009,

13000-500: The right dose to achieve optimal treatment effectiveness with minimized toxic side effects. Some people are overdosed while others are underdosed. For example, in a randomized clinical trial, investigators found 85% of metastatic colorectal cancer patients treated with 5-fluorouracil (5-FU) did not receive the optimal therapeutic dose when dosed by the BSA standard—68% were underdosed and 17% were overdosed. There has been controversy over

13125-666: The same active substance as Adriamycin, but is available in a pegylated liposomal formulation. Celdoxome pegylated liposomal was approved for medical use in the European Union in September 2022. It is also known as hydroxydaunorubicin and hydroxydaunomycin. It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex. Doxorubicin is photosensitive, and containers are often covered by an aluminum bag and/or brown wax paper to prevent light from affecting it. Doxorubicin

13250-429: The same dose of a given drug based on BSA, the concentration of that drug in the bloodstream of one person may be 10 times higher or lower compared to that of the other person. This variability is typical with many chemotherapy drugs dosed by BSA, and, as shown below, was demonstrated in a study of 14 common chemotherapy drugs. The result of this pharmacokinetic variability among people is that many people do not receive

13375-513: The same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin. This liposome-encapsulated form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma. A non-pegylated liposomal doxorubicin, called Myocet, is approved in the European Union and in Canada for

13500-566: The short arm of chromosome 17 (17p13.1). The gene spans 20 kb , with a non-coding exon 1 and a very long first intron of 10 kb, overlapping the Hp53int1 gene. The coding sequence contains five regions showing a high degree of conservation in vertebrates, predominantly in exons 2, 5, 6, 7 and 8, but the sequences found in invertebrates show only distant resemblance to mammalian TP53. TP53 orthologs have been identified in most mammals for which complete genome data are available. In humans,

13625-584: The specter of oncogenic infection . p53 acts as a cellular stress sensor. It is normally kept at low levels by being constantly marked for degradation by the E3 ubiquitin ligase protein MDM2 . p53 is activated in response to myriad stressors – including DNA damage (induced by either UV , IR , or chemical agents such as hydrogen peroxide), oxidative stress , osmotic shock , ribonucleotide depletion, viral lung infections and deregulated oncogene expression. This activation

13750-509: The structure of the compound. A strain of Streptomyces was mutated using N -nitroso- N -methyl urethane, and this new strain produced a different, red-colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea , and the name was later changed to doxorubicin to conform to the established naming convention. Doxorubicin showed better activity than daunorubicin against mouse tumors, and especially solid tumors. It also showed

13875-504: The target of the SV40 virus, a strain that induced development of tumors. The name p53 was given in 1979 describing the apparent molecular mass . The TP53 gene from the mouse was first cloned by Peter Chumakov of The Academy of Sciences of the USSR in 1982, and independently in 1983 by Moshe Oren in collaboration with David Givol ( Weizmann Institute of Science ). The human TP53 gene

14000-418: The transcription of proteins that bind to MDM2 and inhibit its activity. Epigenetic marks like histone methylation can also regulate p53, for example, p53 interacts directly with a repressive Trim24 cofactor that binds histones in regions of the genome that are epigenetically repressed. Trim24 prevents p53 from activating its targets, but only in these regions, effectively giving p53 the ability to 'read out'

14125-430: The treatment of head and neck squamous cell carcinoma . It delivers a functional copy of the p53 gene using an engineered adenovirus . Certain pathogens can also affect the p53 protein that the TP53 gene expresses. One such example, human papillomavirus (HPV), encodes a protein, E6, which binds to the p53 protein and inactivates it. This mechanism, in synergy with the inactivation of the cell cycle regulator pRb by

14250-527: The treatment of metastatic breast cancer in combination with cyclophosphamide , but it has not been approved by the FDA for use in the United States. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same rate of PPE. The minimization of this side effect may allow for one-for-one (1:1) substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil,

14375-473: The use of BSA to calculate chemotherapy doses for people who are obese . Because of their higher BSA, clinicians often arbitrarily reduce the dose prescribed by the BSA formula for fear of overdosing . In many cases, this can result in sub-optimal treatment. Several clinical studies have demonstrated that when chemotherapy dosing is individualized to achieve optimal systemic drug exposure, treatment outcomes are improved and toxic side effects are reduced. In

14500-440: The yield is poor. Since daunorubicin is produced by fermentation , it would be ideal if the bacteria could complete DXR synthesis more effectively. Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis . This inhibits the progression of topoisomerase II , an enzyme which relaxes supercoils in DNA for transcription . Doxorubicin stabilizes the topoisomerase II complex after it has broken

14625-442: The yield of DXR. This is of more than academic interest, because at that time DXR cost about $ 1.37 million per kg and current production in 1999 was 225 kg per annum. More efficient production techniques have brought the price down to $ 1.1 million per kg for the non liposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps, and

14750-613: Was granted orphan drug designation by US FDA. On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zolsketil pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS-related Kaposi's sarcoma. The applicant for this medicinal product

14875-451: Was initially found to be capable of producing the more widely used doxorubicin. This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications , other strains of Streptomyces can produce doxorubicin. His group also cloned many of

15000-465: Was isolated from the area surrounding the Castel del Monte , a 13th-century castle. A new strain of Streptomyces peucetius , which produced a red pigment, was isolated, and an antibiotic from this bacterium was effective against tumors in mice. Since a group of French researchers discovered the same compound at about the same time, the two teams named the compound daunorubicin , combining the name Dauni ,

15125-438: Was originally derived in a 1916 study and attempted to translate medicinal doses established with laboratory animals to equivalent doses for humans. The study only included nine human subjects. When chemotherapy was introduced in the 1950s, the BSA formula was adopted as the official standard for chemotherapy dosing for lack of a better option. The validity of this method in calculating uniform doses has been questioned because

15250-560: Was originally extracted from Taxus brevifolia , the Pacific yew. Now this drug and another in this class, docetaxel , are produced semi-synthetically from a chemical found in the bark of another yew tree, Taxus baccata . Podophyllotoxin is an antineoplastic lignan obtained primarily from the American mayapple ( Podophyllum peltatum ) and Himalayan mayapple ( Sinopodophyllum hexandrum ). It has anti-microtubule activity, and its mechanism

15375-412: Was reduced from 18% in the BSA-dosed group to 4% in the dose-adjusted group and serious hematologic side effects were eliminated. Because of the reduced toxicity, dose-adjusted patients were able to be treated for longer periods of time. BSA-dosed people were treated for a total of 680 months while people in the dose-adjusted group were treated for a total of 791 months. Completing the course of treatment

15500-591: Was significant because it became clear that all daunorubicin-producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing dox A encoding plasmids , but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin-like glycosides . Some triple mutants, that also over-expressed dox A, were able to double

15625-508: Was used in the clinical trials cited above and resulted in significantly improved treatment outcomes. Oncologists are already individualizing dosing of some cancer drugs based on exposure. Carboplatin and busulfan dosing rely upon results from blood tests to calculate the optimal dose for each person. Simple blood tests are also available for dose optimization of methotrexate , 5-FU, paclitaxel , and docetaxel . The serum albumin level immediately prior to chemotherapy administration

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