5,10-methylenetetrahydrofolate/5-fluorouracil combination therapy shows enhanced antitumor activity and lower systemic toxicity with a broad range of cytotoxic drugs

5107 Although 5-fluorouracil (5-FU)/leucovorin (LV) has historically been the treatment mainstay for colorectal and pancreatic cancers, the development of new cytotoxic agents such as CPT-11, oxaliplatin, bevacizumab, and gemcitabine has expanded the therapeutic options available to patients afflicted with these diseases. While combination drug regimens using these new chemotherapeutic agents with 5-FU/LV have been shown to be advantageous, they still are generally not curative and often only show modest treatment benefits over previous treatment options. Furthermore, increased toxicity associated with combination drug regimens is a consequence that must be considered. Thus, methods to enhance anti-tumor activity and/or decrease toxicity of 5-FU-based treatments are still needed. LV, which is a common component to the 5-FU-based drug combinations, is inactive directly and must undergo several metabolic transformations to its active metabolite, thus limiting its full activity. 5,10-methylenetetrahydrofolate (CoFactor™), the active metabolite of LV, promotes 5-FU-mediated anti-tumor activity. Concurrently, CoFactor appears to induce less toxicity than LV, thus making 5-FU/CoFactor a promising therapy for solid tumors. As such, we hypothesized combining 5-FU/CoFactor with newer classes of cytotoxic drugs might have therapeutic advantages over 5-FU/LV. Using in vivo human tumor xenotransplant models for colorectal and pancreatic cancer in athymic nude mice, we examined the antitumor efficacy of 5-FU/CoFactor in combination with the aforementioned cytotoxic agents. We observed that CoFactor-containing combination regimens induced either equivalent or better antitumor responses, as noted by slower tumor growth and increased mouse survival, compared to LV-containing combinations for all drug types tested. Simultaneously, in an in vivo Balb/c systemic toxicity model, 5-FU/CoFactor induced less systemic toxicity than 5-FU/LV either alone or in combination drug regimens. Specifically, we observed lower hematological toxicity including less thrombocytopenia, neutropenia, and lymphopenia. Furthermore, weight loss, a common side-effect associated with 5-FU/LV-based treatments, was quantitatively less severe with drug treatments containing CoFactor. For example, while 5-FU/LV/gemcitabine induced >25% weight loss in 91% of mice, significantly less (p