EFFECTIVE COMBINATION THERAPY OF METASTATIC MURINE SOLID TUMORS WITH EDATREXATE AND THE VINCA ALKALOIDS, VINBLASTINE, NAVELBINE AND VINDESINE

Studies are described in which a new folate analogue, edatrexate (EDX) , in combination with the vinca alkaloids, vinblastine (VBL), navelbin e (NVB) or vindesine (DVA) was evaluated against E0771 mammary adenoca rcinoma, T241 fibrosarcoma and the Lewis lung tumor. Each of the four agents when given individually to animals 3 days after transplant of t hese tumors resulted in increases in survival of 53 - 143%. The relati ve effectiveness of these agents was (in increasing order) VBL, NVB co ngruent-to DVA, EDX, with no long-term survivors obtained with any. Co mbination therapy with EDX and vinca alkaloids required dosage attenua tion but was still markedly more effective. Treatment of E0771 and T24 1 tumors with EDX and either NVB or DVA increased survival 3- to 4-fol d compared with therapy with individual agents and yielded 40-70% long -term survivors, while EDX with VBL increased survival 2- to 3-fold an d yielded 20-40% long-term survivors. Simultaneous or sequential (EDX given 24 h before vinca alkaloid) administration of combined therapy w as equally effective. Sequential administration of these agents at the same doses in the reverse order was highly toxic and required further dosage attenuation which compromised efficacy. Effects of these combi nations against the Lewis Lung tumor were not as pronounced and were s omewhat schedule-dependent. Simultaneous administration of EDX with VB L, NVB or DVA increased survival 2- to 3-fold over that obtained with single agents alone and yielded 10-40% long-term survivors, while sequ ential administration increased survival <2-fold over that obtained wi th single agents and yielded 0-20% long-term survivors. These results suggest that combined therapy with these agents in patients may have a ppreciable utility and provide a basis for further clinical trials.