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Treatment Regimens Including the Multitargeted Antifolate LY231514 in Human Tumor Xenografts

Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285

The scheduling of antifolate antitumor agents, including the new multitargeted autofolate LY231514 (MTA), with 5-fluorouracil was explored in the human MX-1 breast carcinoma and human H460 and Calu-6 non-small cell lung carcinoma xenografts to assess antitumor activity and toxicity (body weight loss). Administration of the antifolate (methotrexate, MTA, or LY309887) 6 h prior to administration of 5-fluorouracil resulted in additive growth delay of the MX-1 tumor when the antifolate was methotrexate or LY309887 and greater-than-additive tumor growth delay (TGD) when the antifolate was MTA. In the H460 tumor, the most effective regimens were a 14-day course of MTA or LY309887 along with 5-fluorouracil administered on the final 5 days. In addition, the simultaneous combination of MTA administered daily for 5 days for 2 weeks with administration of gemcitabine resulted in greater-than-additive H460 TGD. MTA was additive with fractionated radiation therapy in the H460 tumor when the drug was administered prior to each radiation fraction. MTA administered along with paclitaxel produced greater-than-additive H460 TGD and additive responses along with vinorelbine and carboplatin. In the Calu-6 non-small cell lung carcinoma xenograft, MTA administered in combination with cisplatin or oxaliplatin was highly effective, whereas MTA administered in combination with cyclophosphamide, gemcitabine, or doxorubicin produced additive responses. Administration of MTA along with paclitaxel or doxorubicin resulted in additive MX-1 TGD. Thus, MTA appears to be especially effective in combination therapies including 5-fluorouracil or an antitumor platinum complex.

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