Improvements in rational anticancer therapy critically depend upon understanding the principles behind normal tissue toxicity. This project proposes to evaluate several approaches to ameliorating drug toxicity as a means to increasing the therapeautic index. Ara-C will be used as a model drug because of the gastrointestinal toxicity that is associated with its antitumor activity. The Brown Norway rat myeloid leukemia (BNML) will be the primary tumor model in these investigations. Continous infusions of ara-C have good therapeutic activity against established BNML tumors, but are associated with substantial gut toxicity. Prostaglandins have been used in experimental chemotherapy to protect the gut from radiation, but little is known about their protective action against chemotherapeutic agents. We shall determine whether selected prostaglandin analogs are capable of ameliorating gastrointestinal injury induced by long-term continous infusions of ara-C. The dose range and schedule for producing ara-C toxicity will be determined. The nature and extent of damage to the gastrointestinal and hematopoietic systems shall be assessed by histopathology studies to determine villus length and crypt cell number, by diamine oxidase and enteropooling assays, and by leukemic and normal bone marrow CFU-s assays. The dose and schedule of prostaglandin effective in ameliorating ara-C induced gut toxicity as determined by tolerance to toxic ara-C infusions will be established. The ability of ara-C and prostaglandin to increase the survival of rats bearing the BNML shall be evaluated. The biochemical basis for the therapeutic activity of ara-C and prostaglandin combinations will be studied by measuring plasma drug levels and ara-C triphosphate concentrations by HPLC, and by inhibition of DNA synthesis using (3H) dThd in tumor and host tissues. In order to understand the mechanism of prostaglandin gut protection cAMP levels shall be assayed. Correlations between in vivo results and in vitro studies in rat intestinal epithelial and BNML cells in culture will be sought using clonogenic assays. Finally, hyperailimentation which puts the gut to rest, shall be compared with the ability of prostaglandins to cytoprotect the gut from ara-C injury. Information obtained in these studies may aid in the design of clinical therapies to reduce host toxicity.
