Mechanism of hyperthermic potentiation of cisplatin action in cisplatin-sensitive and -resistant tumour cells

Abstract

Summary In this study, the mechanism(s) by which heat increases cis-diamminedichloroplatinum (cisplatin, cDDP) sensitivity in cDDPsensitive and -resistant cell lines of murine as well as human origin were investigated. Heating cells at 430C during cDDP exposure was found to increase drug accumulation significantly in the cDDP-resistant cell lines but had little effect on drug accumulation in the cDDP-sensitive cell lines. DNA adduct formation, however, was significantly increased in all cell lines studied. Furthermore, ongoing formation of platinum (Pt)-DNA adducts after the end of cDDP treatment was enhanced and/or adduct removal was decreased in heated cells, resulting in relatively more DNA damage remaining at 24 h after the end of cDDP exposure. Correlation plots with survival revealed weak correlations with cellular Pt accumulation (r2 = 0.59) and initial Pt-DNA adduct formation (r2 = 0.64). Strong correlations, however, were found with Pt-DNA adducts at 6 h (r2 = 0.97) and 24 h (r2 = 0.89) after the incubation with the drug. In conclusion, the mechanism by which heat sensitizes cells for cDDP action seems to be the sum of multiple factors, which comprise heat effects on accumulation, adduct formation and adduct processing. This mechanism did not seem to differ between cDDP-sensitive and -resistant cells, emphasizing the potential of hyperthermia to reduce cDDP resistance.Keywords: thermochemosensitization; cisplatin resistance; cisplatin accumulation; cisplatin-DNA adducts; adduct repair Hyperthermia can strongly potentiate the cytotoxic action of cisdiamminedichloroplatinum (cisplatin, cDDP) both in vitro and in vivo (reviewed by Engelhardt, 1987). In addition, relatively high heat doses (above 42°C) can (partly) reverse in vitro acquired cDDP resistance (Wallner et al, 1986;Herman et al, 1988;Mansouri et al, 1989;Konings et al, 1993;Hettinga et al, 1994). Resistance to cDDP is a major problem in the clinic and limits the success of this drug. Thus, the combined use of heat and cDDP appears to be an interesting possibility to minimize this problem. The mechanism by which cells become resistant to cDDP has been extensively studied by numerous groups and has been found to be multifactorial (reviewed by Andrews and Howell, 1990), including (combinations of) decreased drug accumulation, increased detoxification of the drug via glutathione (GSH) metabolism or metallothioneins, decreased drug-DNA adduct formation and increased repair of the drug-induced DNA damage. The mechanism(s) by which hyperthermia sensitizes cells to cDDP is (are) less clear. Altered platinum (Pt) accumulation, total Pt-DNA adduct and DNA cross-link formation and/or repair of DNA damage have been reported as a result of combined heat and cDDP treatments (Meyn et al, 1980;Wallner et al, 1986;Herman et al, 1988Herman et al, , 1989Herman et al, , 1990Mann et al, 1988;Mansouri et al, 1989;Eichholtz-Wirth and Hietel, 1990;Los et al, 1993;Takahashi et al, 1993;Ohno et al, 1994). However, the published data are rather contradictory, and in most ...

Peritoneal mesothelioma treated by induction chemotherapy, cytoreductive surgery, and intraperitoneal hyperthermic perfusion

“…In addition, at 40-428C, neoplastic cells become more chemosensitive due to an increase in the intracellular concentration of drugs and in their activation process, especially for alkylating agents, and to alterations in the DNA repair process [23,24]. It has been demonstrated that the formation of platinum-DNA adducts after cisplatin exposure in hyperthermic conditions is enhanced and/or adduct removal is decreased in heated cells, resulting in relatively higher DNA damage [25,26].…”

The role of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in Ovarian Cancer: A Review

“…[23] Cisplatin is a drug that is retained in the peritoneal cavity and its penetration into the adjacent tissues is potentiated by heat in both platinum sensitive and platinum resistant cells lines. [78] The ideal dose of cisplatin has being evaluated in the CHIPASTIN trial. This phase I-II escalating dose trial established that the use of 70 mg/m2 of cisplatin for one hour at 42°C was the most appropriate protocol (Clinical Trials identifier: NCT02217956).…”

Long-term results of intrathoracic chemohyperthermia (ITCH) for the treatment of pleural malignancies

“…Our experience of IPCH shows that the device is safe and reliable for patients with peritoneal carcinomatosis, so we tried this method in the pleural cavity (Gilly et al, 1999). We choose MMC and CDDP because their antitumor effects and intraperitoneal or pleural pharmacokinetics are highly predictable and have been studied most extensively (Rusch et al, 1999;Matsuzaki et al, 1995;Hettinga et al, 1997;Ratto et al, 1999).…”