The effect of the simultaneous addition of a number of clinically useful antibiotics and cancer chemotherapeutic agents on the transport of 2 × 10-6 m methotrexate (4-amino-10-methylpteroyl-glutamic acid; MTX) was studied in L1210 murine leukemia cells in vitro. The results were correlated with the effects of these agents on the antitumor activity of MTX in BALB/cAnN × C57BL/KaLwN F1 mice bearing L1210 leukemia cells using optimal dose levels and schedules.

Utilizing doses that are estimates of achievable peak blood levels in man after conventional single i.v. doses, corticosteroids, cephalothin, l-asparaginase, and the Vinca alkaloids showed the greatest effects on MTX uptake by L1210 leukemia cells, while hydroxyurea, bleomycin, penicillin, and kanamycin appeared to have lesser but significant activities. For example, hydrocortisone at 10-5 and 10-3 m inhibited MTX transport 20 and 65%, respectively. Competitive and dose-related inhibition was clearly evident for this agent. Vincristine and vinblastine at 10-5 m uniquely increased MTX transport by 66 and 49%, respectively, with the effect of vincristine still being significant at 10-9 m. Efflux of MTX-3H from preloaded L1210 leukemia cells was not significantly altered suggesting little effect by any of these agents on intracellular binding of MTX to dihydrofolate reductase enzyme.

The transport inhibitors, hydrocortisone and l-asparaginase, antagonized the antitumor activity of MTX in L1210 leukemia-bearing mice. When hydrocortisone (175 mg/kg i.p. every 4 days, five times) preceded MTX (25 mg/kg i.p. every 4 days, five times) treatment by 180 min, the mean survival time was decreased by 7 days. Conversely, when treatment with the transport enhancer vincristine (1.5 mg/kg i.p. every 4 days, four times) preceded MTX (25 mg/kg i.p. every 4 days, four times) by 30 min, the mean survival time was increased from 23 to 43 days with 30% cures. The time course effects (interval between drug and MTX doses) appear to implicate other factors in addition to transport effects in the antagonism or enhancement of MTX antitumor activity in vivo. These studies suggest that the concurrent use of cancer chemotherapeutic agents and antibiotics may significantly alter cellular transport and ultimately antitumor activity of MTX.

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©1973 American Association for Cancer Research.
1973
Cancer Research, Inc.
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