Methotrexate cytotoxicity

Salicylates, probenecid, and sulfonamides inhibit the renal tubular secretion of methotrexate and may displace it from plasma proteins. Asparaginase inhibits protein synthesis and may protect cells from methotrexate cytotoxicity by delaying progression from Gj-phase to S-phase. Methotrexate may either enhance or inhibit the action of fluorouracil, depending on its sequence of administration. 

Methotrexate Cytotoxic to lymphocytes HematoLoxidty, mucositis, crystalluria... 

Chemotherapeutic agents are grouped by cytotoxic mechanism. The alkylating agents, such as cyclophosphamide [50-18-0] and melphalan [148-82-3] interfere with normal cellular activity by alkylation deoxyribonucleic acid (DNA). Antimetabohtes, interfering with complex metaboHc pathways in the cell, include methotrexate [59-05-2] 5-fluorouracil [51-21-8] and cytosine arabinoside hydrochloride [69-74-9]. Antibiotics such as bleomycin [11056-06-7] and doxombicin [23214-92-8] h.a.ve been used, as have the plant alkaloids vincristine [57-22-7] and vinblastine [865-21-4]. 

Cushing s syndrome Cytotoxic drugs (e.g., methotrexate, cisplatin)... 

Cytotoxic drugs that have been used alone and in combination as adjuvant therapy in breast cancer include doxorubicin, epirubicin, cyclophosphamide, methotrexate, fluorouracil,... 

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. 

Leucovorin (folinic acid) - enzyme cofactor for thymidylate synthase rescues from methotrexate toxicity potentiates cytotoxicity of fluoro— pyrimidines -occasional nausea -skin rash -headache -rare allergic reactions... 

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. 

Gahvan, J. (1980) Evidence for the cytotoxic activity of polyglutamate derivatives of methotrexate. MoZecnZar Pharmaco/ogy. 17, 105-110. 

Methotrexate is a cytotoxic agent that may cause pulmonary toxicity and therefore patients are advised to contact the doctor if cough develops. 

Ciclosporin, a calcineurin inhibitor, is a potent immunosuppressant useful in the prevention of rejection in organ transplants and grafting procedures. Ciclosporin is markedly nephrotoxic. Vincristine is a vinca alkaloid cytotoxic agent fluorouracil and methotrexate are both antimetabolite cytotoxic agents and bleomycin is a cytotoxic antibiotic. 

Presumably, any cytotoxic substance that destroys bone marrow and lymphoid tissue may be used as an immunosuppressant. Among these drugs, the most widely used primarily for autoimmune diseases are vincristine, methotrexate, and cytarabine. However, their use should be considered experimental. Only methotrexate is seriously and sufficiently recognized as an initial drug for treating rheumatoid arthritis. 

Malignant lymphomas Malignant lymphomas, which may regress following withdrawal of methotrexate, may occur in patients receiving low-dose methotrexate and, thus, may not require cytotoxic treatment. Discontinue methotrexate first and, if the lymphoma does not regress, institute appropriate treatment. 

Tumor lysis syndrome Like other cytotoxic drugs, methotrexate may induce tumor lysis syndrome in patients with rapidly growing tumors. 

In phase II studies with topotecan alone, there is cytotoxic activity in lung cancer with intermittent dose schedules (33), as well as in lung cancer patients with topoisomerase II refractory disease (34). In advanced head and neck cancer topotecan is well-tolerated and has single-agent activity similar to that of cisplatin, 5-fluorouracil, and methotrexate... 

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. 

Cytotoxic agents which are used both for the treatment of cancer as for their immunosuppressive activity include cyclophosphamide, methotrexate, chlorambucil, vincristine, vinblastine and dactinomycin. 

Some drugs that exert their maximum cytotoxicity during the S-phase of the cycle also prevent cells from progressing through the cell cycle to the S-phase this is accomplished by sublethal inhibition of RNA and protein synthesis. The antimetabolites methotrexate, fluo-rouracU, and mercaptopurine all can inhibit RNA synthesis in Gi- and Gz-phases and inhibit DNA synthesis during S-phase. This inhibition of cell cycle progression actually may result in reduced cytotoxicity, and such agents have been termed S-phase-specific but self-limited. 

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. 

The formation of polyglutamic acid conjugates of methotrexate has been observed in tumor cells and in the liver and may be an important determinant of cytotoxicity. These methotrexate polyglutamates are retained in the cell and are also potent inhibitors of dUiy-drofolate reductase. 

Many drugs interact with folate to affect its absorption, antagonize its biochemical activity, or increase its loss from the body. These drugs include ethanol, phenytoin, and oral contraceptives. Salicylates can compete with foUc acid for plasma protein binding. Methotrexate, a cytotoxic agent, is a folate antagonist that inhibits the biosynthesis of this coenzyme. 

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