levoleucovorin and Hypoxia

Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive and lethal cancers with very few available treatments. For many decades, gemcitabine was the only treatment for patients with PDAC. A recent attempt to improve patient survival by combining this chemotherapy with FOLFIRINOX and nab-paclitaxel failed and instead resulted in increased toxicity. Novel therapies are urgently required to improve PDAC patient survival. New treatments in other cancers such as melanoma, non-small-cell lung cancer, and renal cancer have emerged, based on immunotherapy targeting the immune checkpoints cytotoxic T-lymphocyte-associated antigen 4 or programmed death 1 ligand. However, the first clinical trials using such immune checkpoint inhibitors in PDAC have had limited success. Resistance to immunotherapy in PDAC remains unclear but could be due to tissue components (cancer-associated fibroblasts, desmoplasia, hypoxia) and to the imbalance between immunosuppressive and effector immune populations in the tumor microenvironment. In this review, we analyzed the presence of "good and bad immunological cops" in PDAC and discussed the significance of changes in their balance.

Topics: Albumins; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Pancreatic Ductal; Cell Cycle Checkpoints; Clinical Trials as Topic; Deoxycytidine; Fluorouracil; Gemcitabine; Humans; Hypoxia; Immunotherapy; Irinotecan; Leucovorin; Oxaliplatin; Paclitaxel; Pancreatic Neoplasms; Tumor Microenvironment

Tumor hypoxia activates hypoxia-inducible factors (Hifs), which induce a range of malignant changes including vascular abnormalities. Here, we determine whether inhibition of the hypoxic tumor response through myo-inositol trispyrophosphate (ITPP), a compound with antihypoxic properties, is able to cause prolonged vascular normalization that can be exploited to improve standard-of-care treatment.. We tested ITPP on two syngeneic orthotopic mouse models of lethal colorectal cancer liver metastasis. Tumors were monitored by MRI and analyzed for the hypoxic response and their malignant potential. A Hif activator and in vitro assays were used to define the working mode of ITPP. Hypoxic response and vasculature were re-evaluated 4 weeks after treatment. Finally, we determined survival following ITPP monotherapy, FOLFOX monotherapy, FOLFOX plus Vegf antibody, and FOLFOX plus ITPP, both overlapping and sequential.. ITPP reduced tumor load, efficiently inhibited the hypoxic response, and improved survival. These effects were lost when mice were pretreated with a Hif activator. Its immediate effects on the hypoxic response, including an apparent normalization of tumor vasculature, persisted for at least 4 weeks after treatment cessation. Compared with FOLFOX alone, Vegf antibody combined with FOLFOX prolonged survival by <30%, whereas ITPP combined with FOLFOX extended survival by >140%, regardless of whether FOLFOX was given in overlap or after ITPP exposure.. Our findings reveal a truly antihypoxic mechanism for ITPP and demonstrate the capacity of this nontoxic compound to potentiate the efficacy of existing anticancer treatment in a way amenable to clinical translation. Clin Cancer Res; 22(23); 5887-97. ©2016 AACR.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Cell Line; Colonic Neoplasms; Disease Models, Animal; Fluorouracil; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit; Inositol Phosphates; Leucovorin; Liver; Liver Neoplasms; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Organoplatinum Compounds; Oxygen; Tumor Burden; Vascular Endothelial Growth Factor A

Limited penetration of anticancer drugs through tumour tissue is an important factor that may limit therapeutic effects against solid tumours. Here we report studies of the penetration of radiolabelled methotrexate through multicellular layers (MCL) of murine EMT-6 and human MCF-7 cells grown on semiporous teflon membranes. The penetration of methotrexate was only about 25% of that through the teflon membrane alone after 6 hr. This was true for all methotrexate concentrations examined from 10 microM to 3 mM. The presence of folic acid at concentrations above 0.1 mM and of acidic conditions decreased the uptake of methotrexate into single cells and enhanced tissue penetration. Hypoxic conditions and the presence of folinic acid (leucovorin) had no effect on penetration or uptake of methotrexate. Our data provide evidence that tissue penetration of methotrexate is through the extracellular space, that its distribution in solid tissue may be limited and that it may be possible to improve its tissue penetration.

Topics: Animals; Antimetabolites, Antineoplastic; Breast Neoplasms; Cell Culture Techniques; Cell Survival; Dose-Response Relationship, Drug; Female; Folic Acid; Humans; Hydrogen-Ion Concentration; Hypoxia; Leucovorin; Mammary Neoplasms, Animal; Methotrexate; Mice; Polytetrafluoroethylene; Time Factors; Tumor Cells, Cultured

Topics: Aerobiosis; Animals; Carcinoma 256, Walker; Dietary Carbohydrates; Energy Metabolism; Extracellular Space; Female; Glucose; Glycolysis; Hydrogen-Ion Concentration; Hypoxia; Injections, Subcutaneous; Lactates; Leucovorin; Ligation; Methotrexate; Neoplasm Transplantation; Phrenic Nerve; Pulmonary Artery; Rats; Remission, Spontaneous