Methotrexate is now used widely for the treatment of acute leukemia, non-Hodgkin's lymphoma, osteogenic sarcoma, choriocarcinoma, breast carcinoma, pulmonary and epidermoid carcinoma, and intrathecal chemotherapy. It is also useful in bone marrow transplantation, severe psoriasis, rheumatoid arthritis, dermatomyositis, Wegener's granulomatosis and sarcoidosis. The recent dramatic intensification of methotrexate therapy can be attributed in part to advances in our understanding of the clinical pharmacology of the folate antagonists, as well as to the combination of positive results and their effective dissemination to medical oncologists. The review summarizes the pharmacologic findings and illustrates how they are currently being applied to the treatment of malignant disease.

The clinical pharmacology of methotrexate: new applications of an old drug.

High-dose methotrexate (HDMTX) with leucovorin (LV) rescue has been used as a therapeutic strategy in oncology for more than a decade. Administration of HDMTX results in tumoricidal plasma concentrations of the drug without significant host toxicity, provided that plasma MTX levels are monitored and LV rescue is properly administered. The original premise of LV rescue was that the provision of reduced folate to normal cells would circumvent the metabolic block produced by MTX and allow resumption of DNA synthesis, although the presumed therapeutic selectivity of leucovorin has not yet been adequately explained. Despite a strong pharmacologic rationale and a vast clinical experience, HDMTX with leucovorin rescue has not been shown to be unequivocally superior to conventional doses of MTX in any clinical situation except, perhaps, for treatment of osteogenic sarcoma and childhood acute leukemia. While HDMTX is an important component of effective treatment regimens for these diseases, its precise contribution to the success of these regimens remains undefined. Although HDMTX can theoretically overcome all known mechanisms of MTX resistance, no data exist to suggest that this can be accomplished in the clinic. Thus, this well-known but poorly understood treatment regimen must remain a subject of clinical investigation rather than a part of routine clinical practice.

High-dose methotrexate: a critical reappraisal.

From 1982 to 1989, 97 patients with extremity-localized, high-grade osteosarcoma were treated according to the T-10 protocol. Two thirds of the patients consisted of the near-complete national patient materials from Norway and Finland. Eighty patients (82%) received four courses of high-dose methotrexate (HD MTX, 8 to 12 g/m2) at weekly intervals as their only preoperative treatment, and 77 patients (79%) were assessable for histologic response grading according to Rosen et al (Cancer 49:1221-1230, 1991). Observed histologic response was no certain chemotherapy effect (grade I) in 21%, grade II effect in 62%, and grade III or IV effect in 17%. Nonresponders had significantly lower serum MTX concentrations after 24 and 48 hours than responders; the significance of the difference at 48 hours was maintained in a multivariate analysis. After a median follow-up of 45 months, projected 5-year overall and relapse-free survival for all patients were 64% and 54%, respectively. Patients with a good response to preoperative chemotherapy (grade III/IV) had a significantly better survival than grade I/II responders, despite a switch to postoperative cisplatin/doxorubicin chemotherapy in the latter group. These results were obtained in a largely nonselected group of patients. We conclude that a good initial chemotherapy effect is important for the final outcome in osteosarcoma, and that HD MTX alone is insufficient preoperative treatment for the majority of patients. The individual MTX excretion rate is of importance for tumor response, suggesting a dose-response relationship for HD MTX treatment.

Treatment of osteosarcoma of the extremities with the T-10 protocol, with emphasis on the effects of preoperative chemotherapy with single-agent high-dose methotrexate: a Scandinavian Sarcoma Group study.

The absorption of methotrexate following intramuscular injection and oral administration of small doses (>30mg/m2) is rapid and complete, whereas with oral doses in excess of 80mg/m2 absorption is less than complete. Pretreatment with oral neomycin decreases and with kanamycin increases the gastrointestinal absorption of oral methotrexate. The plasma disposition of methotrexate is multiexponential. Due to differences in sampling schedule and assay methods, widely varying estimates of elimination half-life (tJ/2β of 6 to 69 hours of methotrexate have been reported. The long half-life may either be due to enterohepatic circulation of methotrexate and/or its metabolites or a slow elimination of dihydrofolate reductase (DHFR) bound methotrexate. The plasma clearance of methotrexate following small clinical doses is about 80ml/min, but may become saturated at high doses (20g). During high dose infusions, the peak plasma level is proportional to doses up to 200mg/kg. Methotrexate is transported across cellular membranes via a carrier-mediated active type process. At high concentrations, when the carrier route is saturated, passive diffusion assumes greater importance. Methotrexate is not highly bound to plasma proteins (∼50%). However, being highly ionised at physiological pH, the drug does not accumulate in the cerebrospinal fluid to any appreciable extent, necessitating intrathecal administration in the treatment of cerebral and meningeal metastases. Renal excretion is the major route of elimination for methotrexate (∼80% ); the drug being actively secreted in the renal tubule by the general organic acid transport system. Hence, the renal clearance of methotrexate is decreased by the concomitant administration of organic acids, such as salicylate. The renal clearance of methotrexate is correlated with endogenous creatinine clearance which may provide a guideline to dosage adjustments according to renal function and age. With high dose methotrexate, routine administration of fluid and/or bicarbonate is recommended to prevent intratubular precipitation of the drug. Biliary excretion of methotrexate constitutes less than 10% of the administered dose. Other extrarenal routes of excretion such as secretion into human breast milk and saliva are negligible. About a third of an oral dose of methotrexate is metabolised by intestinal bacteria during absorption. The major metabolite is 4-amino-4-deoxy-N10-methylpteroic acid. Small amounts (<11%) of 7 -hydroxymethotrexate have also been found in urine of patients receiving high dose methotrexate therapy. Except for the poly-γ-glutamates, all of the reported metabolites are less effective than methotrexate as an inhibitor of dihydrofolate reductase. As determined by inhibition of DNA synthesis, normal tissues are sensitive to low levels of methotrexate (∼10−8M) Furthermore, toxicity with methotrexate is related to duration of exposure as well as to the dose or plasma concentration. Impurities, such as methopterin and other byproducts of the synthetic process have been found in commercial parenteral dosage forms of methotrexate. The clinical significance of these impurities requires further study. For a phase-specific chemotherapeutic agent such as methotrexate, effective plasma levels of the drug should be maintained during the proliferative phase of the tumour cell cycle to achieve a maximum cytotoxic effect. Monitoring the plasma level of methotrexate, particularly during high dose therapy, may provide information regarding impending toxicity and the need for extended citrovorum factor rescue.

Clinical pharmacokinetics of methotrexate

Methotrexate: clinical pharmacology, current status and therapeutic guidelines.

Methotrexate toxicity: correlation with duration of administration, plasma levels, dose and excretion pattern.

The value of adriamycin in overcoming resistance to methotrexate in tissue culture.

The difference between "selective folinic acid protection" and "folinic acid rescue" in L5178Y cells culture.

Adriamycin-14-octanoate (ADR-OCT) was superior to adriamycin (ADR) in reducing the viability of L5178Y cells resistant to methotrexate (MTX). This effect was seen in logarithmically growing and plateau-phase cultures and increased both with dose and duration of exposure. Both ADR-OCT and ADR were effective inhibitors of the exogenous Escherichia coli DNA-dependent RNA polymerases in vitro and of the endogenous polymerase in mammalian cultured cells. Drug concentrations required for approximately 50% enzyme inhibition in both systems were comparable for both agents, being of the order of 10(-5) M. These experimental studies suggested that ADR-OCT may be a valuable agent for treating neoplasms resistant to MTX.

L.A. Price

Papers

Methotrexate toxicity: correlation with duration of administration, plasma levels, dose and excretion pattern.

The value of adriamycin in overcoming resistance to methotrexate in tissue culture.

The difference between "selective folinic acid protection" and "folinic acid rescue" in L5178Y cells culture.

Superiority of Adriamycin-14-octanoate Over Adriamycin in Reducing Viability of Methotrexate-Resistant L5178Y Cells: Brief Communication