Methotrexate sarcomas

Cyclophosphamide is a component of CMF (cyclophosphamide, methotrexate, 5-fluorouracil) and other drug combinations used in the treatment of breast cancer. Cyclophosphamide in combination may produce complete remissions in some patients with ovarian cancer and oat cell (small cell) lung cancer. Other tumors in which benehcial results have been reported include non-oat cell lung cancers, various sarcomas, neuroblastoma, and carcinomas of the testes, cervix, and bladder. Cyclophosphamide also can be employed as an alternative to azathioprine in suppressing immunological rejection of transplant organs. 

High-dose methotrexate administration with leucovorin rescue has produced remissions in 30% of patients with metastatic osteogenic sarcoma. 

Methotrexate Inhibits DHFR inhibits TS inhibits de novo purine nucleotide synthesis Breast cancer, head and neck cancer, osteogenic sarcoma, primary central nervous system lymphoma, non-Hodgkin s lymphoma, bladder cancer, chorioca rcinoma Mucositis, diarrhea, myelosuppression with neutropenia and thrombocytopenia... 

Osteogenic sarcoma Doxorubicin, or methotrexate with leucovorin rescue initiated after surgery Cyclophosphamide, dacarbazine, interferon, ifosfamide plus mesna1... 

Miscellaneous sarcomas Doxorubicin plus dacarbazine Methotrexate, dactinomycin, ifosfamide plus mesna,1 vincristine, vinblastine... 

Therapeutic applications Dactinomycin is used in combination with surgery and vincristine (see p. 390) for the treatment of Wilm s tumor. With methotrexate (see p. 378) it is effective in the treatment of gestational choriocarcinoma. Some soft-tissue sarcomas also respond. 

Endometrial Ewing s sarcomao" Gastric Head and neck,squamous cell Islet cell (pancreas) Kaposi s sarcoma Doxorubicin cisplatin + cyclophosphamide CAV Cyclophosphamide (or Ifosfamide) + doxorubicin (Adriamycin) + vincristine CF epirubidri + cisplatin 5-fluorouraci1 Cisplatin + S-fluorouracil Methotrexate Screptozotocin + S-fluorouracil Etoposide or interferon affa or vinblastine ABV doxorubicin (Adriamycin) + bteomycin + vincristine or vinblastine... 

Hilton M A, Bertolone S, Patel CC. Daily profiles of plasma phenylalanine and tyrosine in patients with osteogenic sarcoma during treatment with high-dose methotrexate-citrovorum rescue. Med Pediatr Oncol 1989 17(4) 265-70. 

The rescue of normal, but not tumor, cells from methotrexate toxicity by folinic acid is partly explained by differences in membrane transport. For example, osteogenic sarcoma cells (which do not respond to conventional doses of methotrexate treatment) are not rescued by folinic acid administered after methotrexate, presumably owing to the absence of transport sites for folinic acid in the neoplastic cells. The therapeutic effects of administration of methotrexate and rescue with folinic acid are superior to those of methotrexate alone. Resistance to methotrexate can develop from increased activity of dihydrofolate reductase, synthesis of an enzyme having a lower affinity for the inhibitor, decreased transport of the drug into tumor cells, decreased degradation of the reductase, and genetic amplification of the gene for dihydrofolate reductase. 

Folate analogues, such as methotrexate (Figure 27-3), are folate antagonists. They block production of FH2 and FH4 by dihydrofolate reductase and lead to diminished purine biosynthesis (inhibition of reactions 3 and 9 in Figure 27-8). Methotrexate also affects metabolism of amino acids and pyrimidine (inhibition of thymidylate synthesis) and inhibits DNA, RNA, and protein synthesis. It is effective in the treatment of breast cancer, cancer of the head and neck, choriocarcinoma, osteogenic sarcoma, and acute forms of leukemia. High doses of methotrexate can be tolerated provided that the patient also receives folinic... 

The classic antifolate methotrexate MTX continues to be an important component of the chemotherapeutic armamentarium for a variety of cancers including pediatric ALL, osteogenic sarcoma, lymphoma, and breast cancer. Raltitrexed, another anti-folate, is used throughout much of the world outside of the United States for advanced colorectal cancer. Finally, Peme-trexed was approved in 2004 for the treatment of pleural mesothelioma and shortly thereafter as a second line treatment for nonsmall cell lung cancer. These drugs mimic the natural folate molecule and in so doing utilize the membrane-bound reduced folate carrier (RFC) protein system to gain entry into the cell. 

Dactinomycin is an antineoplastic agent that is the principal component of the mixture of actinomycins produced by Streptomyces parvullus. It inhibits messenger RNA synthesis. Dactinomycin (0.5 mg/day IV for 5 days), in combination with vincristine, radiotherapy, and surgery, is used in Wilms tumor in conjunction with vincristine, cyclophosphamide, and doxorubicin, it is used in choriocarcinoma in combination with methotrexate, it is used in testicular carcinoma and in combination with cyclophosphamide and radiotherapy, it is used in Ewing s sarcoma. Dactinomycin inhibits messenger RNA synthesis by anchoring to a purine-pyrimidine (DNA) base pair by intercalation (see Figure 15). The toxicity of dactinomycin increases when combined with radiation therapy. 

The most important clinical use of dactinomycin is in the treatment of rhabdomyosarcoma and Wilms tumor in children, where it is curative in combination with primary surgery, radiotherapy, and other drugs, particularly vincristine and cyclophosphamide. Antineoplastic activity has been noted in Ewing s tumor, Kaposi s sarcoma, and soft-tissue sarcomas. Dactinomycin can be effective in women with advanced cases of choriocarcinoma in combination with methotrexate. Dactinomycin also has been used as an immunosuppressant in renal transplants. 

This potent anticancer drug is now widely used in chemotherapy in association with several other drugs (e.g., vinblastine, methotrexate, carboplatine, ifosfamide, or etoposide) in the treatment of Hodgkin s disease (9), of head and neck cancers (JO, 11), of disseminated germ cell tumors (12), and of poor-prognosis epidemic Kaposi s sarcoma (13) (for previous articles on the clinical use of BLM, see references listed in Refs. 9-13). 

Antifolate chemotherapy produced the first cure of a solid tumor, choriocarcinoma. Introduction of high-dose regimens with rescue of host toxicity by the reduced folate, leucovorin (folinic acid, citrovorum factor, 5-formyl tetrahydrofolate, N -formyl FH ), further extended the effectiveness of these drugs to both systemic and CNS lymphomas, osteogenic sarcoma, and leukemias. Most recently, analogs that differ from methotrexate in their transport properties and sites of action have proven useful in treating other cancers. 

Wilm s, Ewing sarcoma, embryonal rhabdomyosarcoma, methotrexate-resistant gestational choriocarcinoma, testicular tumors... 

Intravenous infusion 8 /m over 6 hours Amoxicillin (1 g every 6 hours orally) Osteogenic sarcoma (1) 56% reduction in methotrexate clearance prolonged and marked enhancement of methotrexate plasma levels acute and subacute methotrexate toxicity 1... 

Intravenous infusion 12 g/m over 4 hours Mezlocillin (330 mg/ g daily) Osteogenic sarcoma (1) Reduced methotrexate clearance increased gastrointestinal toxicity 4... 

Intravenous infusion 15 g over 6 hours Oxacillin (1 g every 8 hours starting 6 hours after methotrexate infusion) Osteogenic sarcoma (1) Rasma methotrexate levels 53-fold higher than in previous cycles without oxacillin fatal acute toxicity (renal failure and aplastic anaemia) 5... 

In human leukaemia, the malignant white blood cells readily develop resistance to methotrexate (4.7) when treated with this drug. At the same time, an excess of DHFR, the enzyme that methotrexate is employed to block, is found in the patient s leucocytes (Bertino et al., 1965). The 200-fold increase in this reductase found in murine sarcoma and lymphoma cells which became resistant through methotrexate treatment, has been traced to induction, by the drug, of extra copies of the gene (Alt et al., 1978). For more on such gene amplification, see Fox (1984), Borst (1984). 

Singh, U.V. et al, 1997. Enhanced antitumor efficacy of methotrexate poly(lactic-co-glycolic) acid injectable gel implants in mice bearing sarcoma-180. Pharm. Scl, 3, 133-136. 

Folic Acid Antagonists - Interest in antimetabolites that interfere with the synthesis of nucleic acids continues. Studies on the transport and uptake of methotrgxate ° and 2,4-diamino-5-(3,4-dichlorophenyl)-6-methylpyrimidine indicate that clinical response is related to cellular uptake of drugl and the resistance of certain cells to methotrexate appears to be due to lack of transport into these cells. Work on other resistant cell lines indicates that resistance can also be due to an increase in cellular content of folate reductase, but no correlation was observed between resistance and the level of other enzymes involved in folate metabolism. Despite these results there is evidence that the ability of methotrexate to kill cells cannot be entirely explained by its inhibition of folate reductase. Leucovorin at appropriately timed intervals improved the therapeutic index of methotrexate in the treatment of head and neck cancer, and lymphosarcoma and reticulum cell sarcoma. The use of methotrexate in the treatment of hormone-refractory metastatic breast carcinoma " and the use of intrathecal methotrexate also appear promising. Oxidation of methotrexate to 7-hydroxymethotrexate by liver aldehyde oxidase is probably a detoxification mechanism. Material previously reported to be tetrahydromethotrexate has now been found to be a mixture of di- and tetrahydromethotrexate, both of which are less effective than methotrexate in the inhibition of folate reductase, but more effective in the inhibition of thymidylate synthetase. ... 

Jaffe, N. and Traggis, D. (1975) Toxicity of high dose methotrexate (NSC-740) and citro-vorum factor (NSC-3590) in osteogenic sarcoma. Cancer Chemother. Rep., 6, 31. 

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