Enzyme patterns in human tissues. IV. Comparison of glycolytic enzymes in surgical biopsies and autopsy specimens.
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H Majima
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The cytotoxic effect of cis-diamminedichloroplatinum(II) on cultured Chinese hamster ovary cells at elevated temperatures: Arrhenius plot analysis.
The effect of cis-diamminedichroloplatinum (II) (cis-DDP) and hyperthermia on cultured Chinese hamster ovary (CHO) cells were investigated. Cells were treated with 6 microM cis-DDP for various durations of time at temperatures ranging from 37 to 43 degrees C, and cell survival curves were determined as a function of treatment time. The cytotoxic effect of cis-DDP increased with increasing temperatures, indicating that hyperthermia enhanced cytotoxicity of cis-DDP. Arrhenius analysis of surviving fraction data (6 microM cis-DDP) yielded activation energies of 61 kcal/M between 37 and 41 degrees C and 213 kcal/M between 41 and 43 degrees C. Further experiments using two different drug concentrations (3 and 12 microM) confirmed these activation energies in these two different temperature ranges. However, the activation energy for 12 microM cis-DDP given in the temperature range 33-37 degrees C was 22 kcal/M, which is smaller than those found above 37 degrees C. This activation energy appeared to be identical to that reported for the degradation or depurination of DNA. The activation energy between 37 and 41 degrees C, i.e. approximately 61 kcal/M, was twice as great as that found for alkylation of thio-TEPA, an alkylating agent. This may indicate that the mechanism of action of cis-DDP differs from that of thio-TEPA. A greater activation energy observed in the range of 41-43 degrees C is most likely attributable to the additive effect of hyperthermia and thermal enhancement for cis-DDP. Although only one data point is available at the temperature above 43 degrees C, it suggests that the activation energy is identical to that for hyperthermia alone.
Animals↗
Cytotoxic effect of 1,3 bis (2-chloroethyl)-N-nitrosourea at elevated temperatures: Arrhenius plot analysis and tumour response.
The effect of hyperthermia on the cytotoxicity of 1,3-bis-(2-chloroethyl)-N-nitrosourea (BCNU) was investigated in vitro and in vivo. Tumour cells were early-generation isotransplants of a spontaneous C3Hf/Sed mouse fibrosarcoma, FSa-II. For in vitro studies, single cell suspensions containing 1.0 x 10(6) cells/ml were treated in a water bath where a desired temperature was maintained by a constant-temperature circulator. Cell survival was determined by lung colony assay immediately thereafter. For in vivo studies the tumour cell suspensions were transplanted into the dorsal site of the C3Hf/Sed mouse foot. Tumours were treated by immersing animal feet into a constant-temperature water bath when tumours reached an average diameter of 4 mm (35 mm3). The tumour growth (TG) time or the time for one-half of the treated tumours to reach 1000 mm3 from initial treatment day was used as an endpoint. BCNU dose-cell survival curve at 37 degrees C was exponential with a D0 of 1.1 microgram/ml. Dose-cell survival curves at 37-43 degrees C were determined as a function of treatment time at pH 6.7 and 7.4. BCNU of 1 microgram/ml was added immediately before treatment. The slope of the survival curve became steeper with increasing temperature, indicating that the cytotoxic effect of BCNU was enhanced by hyperthermia. The Arrhenius plot analysis showed that activation energies at pH 6.7 and 7.4 were 53 and 51 kcal/M, respectively (no significant difference). Of interest in this analysis was that the Arrhenius plot did not show a breaking point which has been observed for other agents. Further investigation demonstrated that the decomposition of BCNU, which has been reported to be essential for production of reactive intermediates, occurred in aqueous medium at elevated temperatures. The magnitude of this decomposition depended on treatment temperature. As a result, preheated BCNU became less cytotoxic with an increase in preheating temperatures. The activation energy for this decomposition was about one-half of the activation energy for BCNU cytotoxicity. Studies in vivo indicated that the effect of BCNU was enhanced with increasing temperatures, and the enhancement was greatest when BCNU was administered i.p. immediately before hyperthermia. A glucose dose of 5 g/kg administered i.p. 60 min before hyperthermia further enhanced the antitumour effect of BCNU.
Animals↗
Interaction between the kinetics of thermotolerance and effect of cis-diamminedichloroplatinum(II) or bleomycin given at 37 or 43 degrees C.
The interaction between the cytotoxic effect of bleomycin (BLM) or cis-diamminedichloroplatinum(II) (cis-DDP) and the kinetics of thermotolerance was studied in cultured Chinese hamster ovary (CHO) cells. Pre-heated cells were treated with cis-DDP or BLM at 37 or 43 degrees C for various times after heating. Pre-heating enhanced cis-DDP cytotoxicity given immediately after heating, but this enhancement decreased within 24 h to an additive level. Cell survival following the initial heating and the second treatment of 'cis-DDP at 43 degrees C was minimal when cis-DDP at 43 degrees C was given immediately after the initial heating, but became higher with increasing treatment interval and reached 'less than additive' level when the treatment interval was extended to more than 24 h. This alteration in cell survival appeared to follow the kinetics of thermotolerance. The interaction between BLM treatment and the kinetics of thermotolerance was similar to that of cis-DDP. However, pre-heating enhanced BLM cytotoxicity much less extensively than cis-DDP cytotoxicity. These results indicate that: (a) pre-heating of cells enhanced drug-toxicity when the drug was given shortly after heating, but the magnitude of this enhancement depended on the drug; (b) pre-heating did not influence the cytotoxicity of drugs given at 37 degrees C; and (c) pre-heating decreased the magnitude of thermal sensitization of drug cytotoxicity. The magnitude of the decrease in thermal sensitization appeared to be parallel to the kinetics of thermotolerance. In this study it was also demonstrated that pre-treatment of CHO cells by cis-DDP or BLM did not alter sensitivity to subsequent drug treatment, hyperthermia or thermochemotherapy.
Animals↗