Antimetabolites toxicity

An antimetabolite interferes with the normal cellular metabolites. For instance, it can act as an inhibitor of one or more enzymes whose substrates are metabolites. Others are incorporated into macromolecules instead of the metabolites. Development of antimetabolites exhibiting anti-cancer activity met with the greatest success for analogues of metabolites involved in the biosynthesis of nucleic acids and of cofactors containing nitrogenous bases. Compounds such as 5-fluorouracyl and methotrexate are remarkably effective against human cancers, even though they feature host toxicity. 

Methotrexate -antifolate antimetabolite cell cycle dependent -bone marrow suppression -nausea and vomiting—mild to moderate -mucocutaneous effects (mucositis, stomatitis, diarrhea) -hepatotoxicity—more common in high-dose therapy -CNS toxicity—dizziness, malaise, blurred vision, encephalopathy -nephrotoxicity—including acute renal failure, particularly at high doses... 

Trimetrexate -antifolate antimetabolite -bone marrow suppression -mucocutaneous effects (mucositis, stomatitis) -nausea and vomiting -fever -maculopapular rash—usually self-limited -anorexia, malaise -above toxicities increased in patient with hypoalbuminemia (<3.5)... 

Methotrexate, an antimetabolite, is indicated for moderate to severe psoriasis. It is particularly beneficial for psoriatic arthritis. It is also indicated for patients refractory to topical or UV therapy. Methotrexate can be administered orally, subcutaneously, or intramuscularly. The starting dose is 7.5 to 15 mg per week, increased incrementally by 2.5 mg every 2 to 4 weeks until response maximal doses are approximately 25 mg/wk. Adverse effects include nausea, vomiting, mucosal ulceration, stomatitis, malaise, headache, macrocytic anemia, and hepatic and pulmonary toxicity. Nausea and macrocytic anemia can be ameliorated by giving oral folic acid 1 to 5 mg/day. Methotrexate should be avoided in patients with active infections and in those with liver disease. It is contraindicated in pregnancy because it is teratogenic. 

Patients with partial deficiency of this enzyme are at risk of developing severe 5-FU-associated toxicity as DPD is responsible for detoxification of pyrimidine-based antimetabolite analogs, such as 5-FU and capecitabine. The onset of toxicity occurs, on average, twice as fast in patients with low DPD activity compared with patients with normal DPD activity (13-16). 

Methotrexate is an antimetabolite, which is metabolised by the renal and hepatic systems and may lead to renal and hepatic toxicities. Liver and renal function tests are therefore carried out for patients who are administered the drug. Methotrexate can lead to myelosuppression and therefore full blood counts must be monitored for patients taking it. 

The reason for the selective toxicity of 6-mercaptopuiine remains to be established, but two factors may be of primary importance. 6-Mercaptopurine is anabolized primarily, if not exclusively, to the monophosphate level, and it is readily catabolized by xanthine oxidase, an enzyme that is low in most cancer cells compared to normal cells. Another factor that must be considered is the metabolic state of the target cells. Actively proliferating leukaemia cells are more sensitive to 6-mercaptopurine, as they are to all antimetabolites, than cells in the so-called Gq or stationary phase. Although this does not explain the difference between 6-mercaptopurine and other purine analogues, it may explain the ineffectiveness of 6-mercaptopurine against solid tumours, most of the cells of which are in the non-dividing state. 

Gemcitabine (Gemzar), an antimetabolite, undergoes metabolic activation to difluorodeoxycytidine triphosphate, which interferes with DNA synthesis and repair, ft is the single most active agent for the treatment of metastatic pancreatic cancer, and it is used as a first-line treatment for both pancreatic and small cell lung cancer. It is administered by intravenous infusion. The dose-limiting toxicity is bone marrow suppression. 

The individual antimetabolites and their respective clinical spectrum and toxicities are presented in Table 54-3. The principal drugs are discussed below. 

Table 54-3 Antimetabolites Clinical Spectrum of Activity and Toxicities. ...

In summary, capecitabine (1), an A -carbamate pyrimidine nucleoside prodrug of cytotoxic antimetabolite 5-fluorouracil, is an FDA-approved anticancer drug that can be administered orally. This compound uses a multilayer of prodrug strategies that not only avoids side effects arising from exposure of toxic metabolites to healthy tissue but is converted to 5-fluorouracil only by enzymes preferentially expressed in many cancer cell types, thus resulting in selective delivery of the drug to tumors. Capecitabine is marketed under the trade name of Xeloda for use in the treatment of metastatic colorectal and breast cancers and metastatic breast cancer that is resistant to paclitaxel or anthracycline therapies. 

From a cultivation of S. sviceus in a 250 1 fermentor almost 0.25 kg of the antibiotic U42126 (122) was isolated [107]. The antimetabolite antibiotic U-42126 significantly increased the life span of tumor-bearing L1210 leukemia mice at low drug levels with no demonstrable signs of toxicity to the hosts. 

Liposomal encapsulation has the potential not only to increase the activity and prolong the residence of the drag in the eye, but also to reduce the intraocular toxicity of certain potent drags such as antimetabolites, antivirals and antibiotics to the retina. For example, liposome-encapsulated amphotericin B produced less toxicity than the commercial amphotericin B solution when injected intravitreally. Liposomes have also been used to study the release and distribution of dyes, which in turn reflect the integrity of the retinal vascular constitution. Direct intravitreal injection of liposomal-encapsulated drags has shown enhanced vitreal levels for extended periods of time in the vitreous of rabbit models. Liposomal encapsulation of the antiviral, HPMPC, reduces the toxic effects to the retina and provides therapeutic levels against CMV retinitis for up to 8 months. 

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