Methotrexate cytotoxicity, effect

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

Cells in S-phase are most sensitive to the cytotoxic effects of methotrexate. RNA and protein synthesis also may be inhibited to some extent and may delay progression through the cell cycle, particularly from Gj to S. 

FLU0R0URACIL METHOTREXATE 1 cytotoxic effect of methotrexate when fluorouracil is administered prior to methotrexate Fluorouracil prevents the conversion of i folates to dihydrofolate Always administer methotrexate prior to fluorouracil... 

Antimetabolites selectively compete for intermediary metabolites critical to immime cell function, exerting a cytotoxic effect. Methotrexate (Folex ), which inhibits folic acid, is the most widely recognized and used drug in this class. Other antimetabolites that may be used in treating uveitis include azathioprine (Imuran ) and mycophe-nolate mofetil (CellCept ), both of which interfere with purine metabolism. 

Methotrexate inhibits DNA synthesis by decreasing avail-ability of pyrimidine nucleotides. Methotrexate competitively inhibits the enzyme dihydrofolate reductase, thus decreasing the concentrations of the tetrahydrofolate essential to the methylation of the pyrimidine nucleotides and consequently the rate of pyrimidine nucleotide synthesis. Leucovorin, a folate analog, is used to rescue host cells from methotrexate inhibition as a synthetic substrate for dihydrofolate reductase, leucovorin administration allows resumption of tetrahydrofolate-dependent synthesis of pyrimidines and reinitiation of DNA synthesis. Methotrexate is a nonspecific cytotoxin, and prolongation of blood levels appropriate to killing tumor cells may lead to severe, unwanted cytotoxic effects such as myelosuppression, gastrointestinal mucositis, and hepatic cirrhosis. 

The antimetabolites are structurally similar to endogenous compounds and are antagonists of folic acid (methotrexate), purines (mercaptopurine, thioguanine), or pyrimidines (fluorouracil, cy-tarabine). Antimetabolites are CCS drugs acting primarily in the S phase of the cell cycle. Their sites of action on DNA synthetic pathways are shown in Figure 55-3. In addition to their cytotoxic effects on neoplastic cells, the anti metabolites also have immunosuppressant actions. Some of the uses of the antimetabolites in neoplastic disease are listed in Table 55-2. 

The clinical importance of the small reduction in theophylline elearanee is uncertain, although it may be worth bearing this in mind in patients maintained at the higher end of the therapeutic levels for theophylline, as they may be more likely to develop toxicity. Aminophylline may reduce methotrexate-induced neurotoxicity, and, dthough there is some evidence that theophylline does not alter the cytotoxic effects of methotrexate, this requires confirmation. One UK manufacturer of methotrexate (licenced for... 

As part of the diet of rats, chicory inulin inhibited tumor formation (colon, mammary, and lung) and potentiated the cytotoxic effects of various common anticancer drugs at subtherapeutic dosages (cyclophosphamide, cytarabine, doxorubicine, 5-fluoroura-cil, methotrexate, and vincristine). ... 

Since the late 1940s, when Farber treated leukemia with methotrexate, cancer therapy with cytotoxic drugs made enormous progress. Chemotherapy is usually integrated with other treatments such as surgery, radiotherapy, and immunotherapy, and it is clear that postsurgery, it is effective with solid tumors. This is due to the fact that only systemic therapy can attack micrometastases. 

The absorption of some drugs may be reduced due to damage of the small intestine. This is most likely after cytotoxic therapy. The absorption of phenytoin and verapamil can be reduced by 20-35% in patients taking cytotoxic drugs such as methotrexate, carmustine, or vinblastine for the treatment of malignant disease. The reduced absorption was accompanied by evidence of loss of therapeutic effect. 

The adverse effects of methotrexate include gastrointestinal complaints, bone marrow suppression, alopecia and nephrotoxicity. The toxic effects of methotrexate may be terminated by administering the fully reduced folate coenzyme leucovorin (folinic acid). Leucovorin rescue permits the administration of high doses of methotrexate, for example in situations where partially resistance has occurred or to obtain cytotoxic concentrations of methotrexate in the CNS. 

Methotrexate is administered by the intravenous, intrathecal, or oral route. Up to 90% of an oral dose is excreted in the urine within 12 hours. The drug is not subject to metabolism, and serum levels are therefore proportionate to dose as long as renal function and hydration status are adequate. Dosages and toxic effects are listed in Table 55-3. The effects of methotrexate can be reversed by administration of leucovorin (citrovorum factor). Leucovorin rescue has been used with accidental overdose or experimentally along with high-dose methotrexate therapy in a protocol intended to rescue normal cells while still leaving the tumor cells subject to its cytotoxic action. 

There is some evidence for the antimuta-genic effects of vanillin for example, in suppressing chromosomal damage induced by methotrexate in the Chinese hamster V79 cell line (Keshava et al, 1998). Inouye et al. (1988) reported the suppression of the induction of micronuclei by mitomycin C (MMC) in mouse bone marrow cells by post-treatment with vanillin. Post-treatment with vanillin at 500mg/kg caused about 50% decrease in the frequency of micronu-cleated polychromatic erythrocytes (MN-PCEs). The suppressant effect was not due to a delay in the formation of MN-PCEs but to the cytotoxic action of vanillin. Vanillin acts as an anticlastogenic factor in vivo. 

---