Cure of advanced L1210 leukemia after correction of abnormal red blood cell deformability

Abstract

Chemotherapeutic efficacy is inversely related to pretreatment tumor burden. A possible contributory factor in chemotherapy resistance is the occurrence of decreased red blood cell deformability in mice with advanced tumors. Poorly deformable red blood cells may prevent adequate drug delivery to tumor cells. Two methods for improving red cell deformability were found in this study. The first involved treatment of L1210 leukemia-bearing mice with red cell metabolic substrates, including inosine, adenosine, glucose, sodium pyruvate, and ascorbic acid. The combination of inosine plus sodium pyruvate (3 mg of each drug in 0.5 cm3 phosphate-buffered saline) was most effective in restoring deformability to normal. Administration of an active chemotherapeutic agent (BCNU or cyclophosphamide) also improved red cell deformability, with maximal restoration occurring 4--5 days after drug treatment. Standard and 50% of standard drug doses were equally effective in restoring deformability. The optimal therapy program for day 7 L1210 leukemia utilized inosine plus sodium pyruvate given 10--15 min before BCNU 15 mg/kg on day 7 and before BCNU 30 mg/kg on day 12. This treatment yielded 44% cures, whereas BCNU alone, in identical dose and schedule, gave no cures. Median survival was 50 days for the inosine-pyruvate-treated mice, as against 30 days for BCNU alone. Therefore, treatment with non-toxic doses of red blood cell metabolic substrates plus optimal timing of chemotherapy, two maneuvers that significantly increased red blood cell deformability, resulted in significant therapeutic benefit.