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Treatment regimens including the multitargeted antifolate LY231514 in human tumor xenografts
1Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. teicher_beverly_a@lilly.com
Abstract:
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.
Insights
The new antifolate, multitargeted autofolate (MTA), shows enhanced antitumor activity when combined with chemotherapy agents like 5-fluorouracil and platinum complexes. This combination therapy strategy offers promising results for various cancers.
Area of Science:
- Oncology
- Pharmacology
- Cancer Research
Background:
- Antifolate antitumor agents are crucial in cancer therapy.
- Optimizing the scheduling and combination of these agents can improve efficacy.
- Multitargeted autofolate (MTA) is a novel antifolate with potential for enhanced antitumor activity.
Purpose of the Study:
- To evaluate the antitumor activity and toxicity of novel multitargeted autofolate (MTA) in combination with other chemotherapeutic agents.
- To explore optimal scheduling of MTA with 5-fluorouracil in various human tumor xenografts.
- To assess MTA's efficacy in combination with gemcitabine, radiation therapy, paclitaxel, vinorelbine, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, and doxorubicin.
Main Methods:
- In vivo studies using human MX-1 breast carcinoma, H460, and Calu-6 non-small cell lung carcinoma xenografts.
- Administration of various antifolates (methotrexate, MTA, LY309887) alone and in combination with 5-fluorouracil at different schedules.
- Assessment of antitumor activity through tumor growth delay (TGD) and toxicity via body weight loss.
Main Results:
- MTA demonstrated greater-than-additive tumor growth delay when combined with 5-fluorouracil in MX-1 xenografts.
- Optimal regimens for H460 tumors involved MTA or LY309887 with 5-fluorouracil, or MTA with gemcitabine.
- MTA showed additive effects with fractionated radiation therapy, paclitaxel, vinorelbine, carboplatin, cisplatin, oxaliplatin, cyclophosphamide, and doxorubicin in different xenograft models.
Conclusions:
- MTA exhibits significant antitumor activity in combination therapies, particularly with 5-fluorouracil and platinum-based agents.
- The scheduling of MTA with other chemotherapeutics is critical for maximizing antitumor effects.
- MTA represents a promising agent for developing novel combination cancer treatment strategies.