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.