The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo

A newly synthesized reagent, KNK437, has been found specifically to inhibit the synthesis of heat shock proteins in vitro. In this study, we investiga ted the effects of KNK437 on the synthesis of heat shock proteins and the i nduction of thermotolerance in transplantable tumors in vivo. SCC VII cells were grown in vivo and transplanted into C3H/He mice. The concentrations o f KNK437 in the tumors and the sera of the mice were examined by high-perfo rmance liquid chromatography, Hsp72 synthesis was examined by Western immun oblot analysis. The response to hyperthermia was evaluated in terms of the delay in tumor growth. KNK437 had low toxicity in vivo. The concentration o f KNK437 in the tumors gradually increased and reached a peak 6 h after i.p . injection. Hsp72 were synthesized 8 h after hyperthermia at 44 degreesC f or 10 min, and their synthesis was inhibited by administration of KNK437 6 h before hyperthermia, At a concentration of 200 mg/kg, KNK437 alone showed no antitumor effects and did not increase the thermosensitivity of nontole rant tumors, The same dose of KNK437 enhanced the antitumor effects of frac tionated heat treatment at 44 degreesC in a synergistic manner. This study strongly suggests the inhibition of thermotolerance via the inhibition of H SP72 in vivo. The inhibition of thermotolerance by KNK437 may help to impro ve the efficacy of clinical fractionated hyperthermia.