The in vitro effect of adriamycin (ADR) and lonidamine alone and in combination, at 37 degrees C and 43 degrees C, was investigated on murine leukemia P388 sensitive (P388/S) and resistant (P388/ADR) to adriamycin. The sensitive and the resistant cells were exposed in vitro with and without the drugs for 1 h at 37 degrees C and 43 degrees C. These cells were inoculated ip (10(6) cells/mouse) into groups of BDF1 mice. Cytotoxic effect of the treatment was assessed on the basis of percentage increase in life span (% ILS) of these animals, compared to the animals receiving cells which did not receive any treatment but exposed only to 37 degrees C for 1 h. It was observed that exposure of P388/ADR cells to lonidamine or adriamycin alone at 43 degrees C for 1 h resulted in greater cell kill, thus enhancing the % ILS of the experimental animals receiving those cells, compared to that of mice receiving the cells exposed to the same drugs for 1 h at 37 degrees C. However, the combination of lonidamine (0.02 mM) and adriamycin (10 micrograms/ml) at 43 degrees C for 1 h showed more than a synergistic effect, resulting in a % ILS of 120. Similar results were seen in the case of P388/S; however, the observations pertaining to P388/ADR are encouraging, since the mode of treatment has reversed the acquired resistance of P388 leukemia cells to adriamycin.