Cisplatin sensitivity and thermochemosensitisation in thermotolerant cDDP-sensitive and -resistant cell lines

Abstract

Summary Development of thermotolerance is an important phenomenon that must be considered when thermochemotherapy with multiple heat treatments is used clinically. To study the effect of thermotolerance on cellular cisplatin (cDDP) sensitivity at 3rC and 43-C in cell lines with different cDDP sensitivities, two Ehrlich ascites tumour cell lines (one with high cDDP sensitivity and one with in vitro acquired cDDP resistance) were used. The results indicate that in both cell lines the state of thermotolerance per se did not affect the cDDP sensitivity at 37C. Thus, general elevations in 'all' heat shock protein levels as found in thermotolerant cells apparently do not influence cDDP sensitivity to a considerable extent. The sensitising effect of a (second) heat treatment given simultaneously with a cDDP treatment was less in thermotolerant cells. Thermal enhancement ratios (TERs) at the 10% survival level for heat doses of 43VC for 30 min or 43VC for 60 min were reduced by a factor of 1.6 and 2.1 in cDDP-resistant and -sensitive thermotolerant cells respectively, as compared with control cells. Thus, protection against heat damage in thermotolerant cells seems to be paralleled by diminished thermal chemosensitisation. Although the effect of thermotolerance on the cDDP-sensitising effect was less pronounced in the resistant cells, a modifying effect on the resistance factor was not achieved.

Effects of combined treatment of chemotherapeutics and hyperthermia on survival and the regulation of heat shock proteins in dunning R3327 prostate carcinoma cells

“…Based on the data given in Figure 2, the thermal enhancement ratios (TERs) at 90% survival, corrected for hyperthermic killing alone, were calculated. For cisplatin (TER 3.5), similar numbers indicating a marked sensitization were also reported by Hettinga et al [25], using Ehrlich ascites tumor cells. For antimetabolites such as 5-fluorouracil, a limited increase of cytotoxicity at hyperthermic temperatures has been suggested, based on the fact that these drugs require an intact cellular metabolism which is known to be reduced during hyperthermia [26].…”

“…These results suggest an attenuated thermal sensitization for all of the chemotherapeutics tested during the status of thermotolerance. In this regard, Hettinga et al [25] reported similar findings in cisplatin-resistant and -sensitive cells.…”

Laser Photo Chemotherapy: An Alternative Treatment for Cancer

“…Under several conditions, including thermo tolerance, a good correlation has been found between the extent and duration of this ``nuclear protein aggregation`` and thermal cell rilling (Hettinga et al, 1995). This nuclear protein aggregation may also be one of the major mechanisms responsible for thermal potentiation of killing by a number of drugs, which is by hampering repair of drug-induced DNA damage (Hettinga et al 1995). Timing of chemotherapy, with respect to potentiation by heat, and of two drugs relative to each other, is critical in determining antitumor efficacy, toxicity, and survival (Bull et al, 2008b;Teischer and Herman, 1992).…”

“…This leads to an increase in protein mass of nuclei isolated from heated cells. Under several conditions, including thermo tolerance, a good correlation has been found between the extent and duration of this ``nuclear protein aggregation`` and thermal cell rilling (Hettinga et al, 1995). This nuclear protein aggregation may also be one of the major mechanisms responsible for thermal potentiation of killing by a number of drugs, which is by hampering repair of drug-induced DNA damage (Hettinga et al 1995).…”

“…Since hyperthermia has the potential to interfere with many mechanisms that cause cisplatin resistance, it may also be a suitable modality to interfere with acquired resistance (Oldenburg et al, 1994;Bull et al, 2008a). Apparently, the mechanisms responsible for hyperthermic cell killing and hyperthermic drug sensitization must, in part, be the same (Hettinga et al, 1995). Heat has been shown to cause denaturation of cellular proteins.…”