Hydralazine combined with hyperthermia enhances the effects of carboquone

Carboquone (CQ) and hyperthermia (HT) are capable of preferentially killing oxygen-deficient cells, both in vitro and in vivo. We examined effects of the combination of CQ and HT on an in vitro hypoxic system and on murine solid tumors using hydralazine (HYD), a vasoactive agent. Under in vitro hypoxic conditions, the combined cytotoxicity of CQ and HT (43 degrees C, for 1 h) was enhanced and the enhancement ratio (ER) for the IC90 of CQ was 21.4-, 9.4-, and 2.6-fold compared to that for CQ alone, CQ under hypoxic condition, and CQ plus HT under aerated cells, respectively. Five mg/kg i.p. HYD reduced the level of tumor blood flow in mice to about 20% of constant level and this reduction persisted for 1 h. In mice bearing B16 melanoma tumors, HYD enhanced tumor susceptibility of the combined therapy of CQ and HT. The ER which was a comparison of tumor growth time in the control group, was 2.3, 3.6 for the two combination groups of 1, 2 mg/kg i.p. CQ, HT (43 degrees C for 20 min), and 5 mg/kg i.p. HYD, respectively. Thus, hyperthermochemotherapy using CQ combined with HYD, seems to selectively attack a solid tumor.