Koishi M, Yokota S, Mae T, Nishimura Y, Kanamori S, Horii N, Shibuya K, Sasai K, Hiraoka M
Department of Radiology, Kyoto City Hospital, Kyoto, Japan.
Clin Cancer Res. 2001 Jan;7(1):215-9.
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.
一种新合成的试剂KNK437已被发现可在体外特异性抑制热休克蛋白的合成。在本研究中，我们调查了KNK437对热休克蛋白合成的影响以及对体内可移植肿瘤热耐受诱导的影响。SCC VII细胞在体内生长并移植到C3H/He小鼠体内。通过高效液相色谱法检测小鼠肿瘤和血清中KNK437的浓度。通过蛋白质免疫印迹分析检测Hsp72的合成。根据肿瘤生长延迟情况评估对热疗的反应。KNK437在体内毒性较低。腹腔注射后，肿瘤中KNK437的浓度逐渐升高，并在6小时后达到峰值。在44℃热疗10分钟后8小时合成Hsp72，在热疗前6小时给予KNK437可抑制其合成。在浓度为200mg/kg时，单独使用KNK437没有抗肿瘤作用，也没有增加未耐受肿瘤的热敏感性。相同剂量的KNK437以协同方式增强了44℃分次热疗的抗肿瘤作用。这项研究强烈表明，在体内通过抑制HSP72可抑制热耐受。KNK437对热耐受的抑制可能有助于提高临床分次热疗的疗效。
