The Effects of KNK437, a Novel Inhibitor of Heat Shock Protein Synthesis, on the Acquisition of Thermotolerance in a Murine Transplantable Tumor in Vivo

• Published in: Clinical cancer research 2001-01, Vol.7 (1), p.215-219
• Main Authors: KOISHI, Mototsugu, YOKOTA, Shin'Ichi, MAE, Tatsumasa, NISHIMURA, Yasumasa, KANAMORI, Shuuichi, HORII, Naotoshi, SHIBUYA, Keiko, SASAI, Keisuke, HIRAOKA, Masahiro
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Benzhydryl Compounds - chemistry; Benzhydryl Compounds - pharmacology; Biological and medical sciences; Cell Division - drug effects; Chromatography, High Pressure Liquid; Combined treatments (chemotherapy of immunotherapy associated with an other treatment); Electrophoresis, Polyacrylamide Gel; Fever; Heat-Shock Proteins - antagonists & inhibitors; Heat-Shock Proteins - metabolism; Humans; Immunoblotting; Injections, Subcutaneous; Male; Medical sciences; Mice; Mice, Inbred C3H; Mice, Inbred ICR; Molecular Structure; Neoplasm Transplantation; Pharmacology. Drug treatments; Pyrrolidinones - chemistry; Pyrrolidinones - pharmacology; Temperature; Tumor Cells, Cultured - drug effects
• ISSN: 1078-0432; 1557-3265

A newly synthesized reagent, KNK437, has been found specifically to inhibit the synthesis of heat shock proteins in vitro . In this study, we investigated the effects of KNK437 on the synthesis of heat shock proteins and the induction of thermotolerance in transplantable tumors in vivo . SCC VII cells were grown in vivo and transplanted into C3H/He mice. The concentrations of KNK437 in the tumors and the sera of the mice were examined by high-performance liquid chromatography. Hsp72 synthesis was examined by Western immunoblot analysis. The response to hyperthermia was evaluated in terms of the delay in tumor growth. KNK437 had low toxicity in vivo. The concentration of 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°C for 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 nontolerant tumors. The same dose of KNK437 enhanced the antitumor effects of fractionated heat treatment at 44°C in a synergistic manner. This study strongly suggests the inhibition of thermotolerance via the inhibition of HSP72 in vivo . The inhibition of thermotolerance by KNK437 may help to improve the efficacy of clinical fractionated hyperthermia.