The effects of hyperthermia and heat-shock protein expression on Adriamycin pharmacokinetics

The effect of hyperthermia on the pharmacokinetics of the antineoplastic drug, Adriamycin, was examined. The distribution of Adriamycin to the tissues was increased in dogs treated with mild whole-body hyperthermia (42°C for 1 hr). Although peak duodenal drug concentration was increased in dogs treated with concurrent hyperthermia, no overt toxicity to the duodenum was demonstrated using select enzyme assays or histologic examination. A slight, nonstatistically significant depression of cell turnover was demonstrated in duodenal biopsies from dogs treated with Adriamycin or Adriamycin combined with whole-body hyperthermia. The effect of local hyperthermia (43.5°C for 1 hr) on Adriamycin concentration in an in vivo rat mammary tumor model was also examined. Prior hyperthermia was seen to reduce Adriamycin concentrations in tumors when Adriamycin was administered 3 hr after local hyperthermia. The production of HSP 70 was also demonstrated in tumors 3 hr after 1 or 2 hyperthermia treatments. Decreased Adriamycin concentration was not due to decreased blood flow to tumors following local hyperthermia as demonstrated by radioactive microsphere techniques. In conjunction with the above studies an HPLC method based on fluorescence detection was developed for small tissue biopsies, plasma, and tumor samples. A fluorescence-activated cell sorter (FACS) technique was also developed for Adriamycin determination in tumor samples. A new method for use of a Nd:YAG laser with accompanying surface cooling to heat superficial tumors is also described.