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The effects of KNK437, a novel inhibitor of heat shock protein synthesis, on the acquisition of thermotolerance in a murine transplantable tumor in vivo.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2001 Jan; Vol. 7 (1), pp. 215-9. - Publication Year :
- 2001
-
Abstract
- 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 degrees 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 degrees 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.
- Subjects :
- Animals
Benzhydryl Compounds chemistry
Cell Division drug effects
Chromatography, High Pressure Liquid
Electrophoresis, Polyacrylamide Gel
Fever
Heat-Shock Proteins metabolism
Humans
Immunoblotting
Injections, Subcutaneous
Male
Mice
Mice, Inbred C3H
Mice, Inbred ICR
Molecular Structure
Neoplasm Transplantation
Pyrrolidinones chemistry
Temperature
Benzhydryl Compounds pharmacology
Heat-Shock Proteins antagonists & inhibitors
Pyrrolidinones pharmacology
Tumor Cells, Cultured drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1078-0432
- Volume :
- 7
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 11205912