MTA (LY231514) in combination treatment regimens using human tumor xenografts and the EMT-6 murine mammary carcinoma.

An important component in the development of a new anticancer drug is an understanding of its potential for inclusion in combination treatment regimens. LY231514, a multitargeted antifolate (MTA), was tested in combination with cisplatin, methotrexate, 5-fluorouracil, paclitaxel, docetaxel, doxorubicin, LY329201 (a glycinamide ribonucleotide formyltransferase [GARFT] inhibitor), and fractionated radiation therapy in vivo using EMT-6 mammary carcinoma, human HCT 116 colon carcinoma, and human H460 nonsmall cell lung carcinoma grown as xenografts in nude mice. Isobologram methodology was used to determine the additivity or synergy of the combination regimens. MTA administered with cisplatin, paclitaxel, docetaxel, or fractionated radiation therapy produced additive to greater than additive tumor response by tumor cell survival assay and tumor growth delay. While an additive tumor response was observed when MTA was administered with methotrexate, synergistic tumor responses were seen when MTA was administered with the GARFT inhibitor, LY329201, or with the topoisomerase I inhibitor, irinotecan. MTA was administered in combination with full doses of each anticancer agent studied, with no evidence of increased toxicity resulting from the combination.