Effect of hyperthermia on intracellular drug accumulation and chemosensitivity in drug-sensitive and drug-resistant P388 leukaemia cell lines

Abstract

Enhancements of the drug-induced cytotoxicity and modifications of drug transmembrane equilibria caused by hyperthermic treatment were analysed on P388/S and P388/R murine leukaemia cell lines. The P388/R cell line was derived from the P388/S cell line by drug selection of mutant, drug-resistant clones; it expresses a pleiotropic drug resistance towards some chemotherapeutic drugs such as doxorubicin, daunorubicin and etoposide, but is only weakly resistant towards other drugs as cis-diammine-dichloroplatinum. Hyperthermic treatment enhanced the drug cytotoxic effects much more on the P388/R cell line than on the P388/S line, but the cytotoxic enhancements were consistent only for the drug towards which the P388/R cell line expresses pleiotropic resistance. Intracellular drug accumulation analysis and drug transmembrane equilibria determinations indicated that the resistance of both cell lines to the intracellular drug was not affected by hyperthermic treatment, whereas variations in drug influx, but not in drug extrusion, were induced by heat treatment. The study suggested, therefore, that hyperthermia does not modify intracellular chemosensitivity of either cell line, but acts on membrane permeability by facilitating attainment of the intracellular drug concentrations needed to cause the cytotoxic effect.

Radio-frequency Ablation Increases Intratumoral Liposomal Doxorubicin Accumulation in a Rat Breast Tumor Model

“…Were such a mechanism responsible, increased accumulation of the low-molecular-weight free doxorubicin would have been observed. Rather, this result supports the contention that the liposome delivery vector used in our study further enhances local drug accumulation in the RF-heated tumor (30,37).…”

Percutaneous Tumor Ablation: Increased Necrosis with Combined Radio-frequency Ablation and Intravenous Liposomal Doxorubicin in a Rat Breast Tumor Model

“…While findings in this previous study (16) conclusively demonstrated synergism between RF heating and unencapsulated intratumoral doxorubicin, in view of the prior discussion, the newer results of this study suggest that very little doxorubicin may be needed to potentiate synergistic tumor destruction. One reason, which could also account for the lack of effect observed with liposomal doxorubicin or unencapsulated doxorubicin alone, is that the cell line used for the study was relatively resistant to doxorubicin, owing to a multidrug-resistant membrane protein that under normal conditions rapidly clears intracellular doxorubicin (32). RF heating could damage this pump and allow intracellular doxorubicin accumulation.…”

Combination radiofrequency thermal ablation and adjuvant IV liposomal doxorubicin increases tissue coagulation and intratumoural drug accumulation

“…Thus, improved treatment effect is at least in part due to other, non-vascular mechanisms. For many tumour cell lines, doxorubicin is actively pumped out of cells by the multi-drug resistance membrane protein, which can be transiently damaged by heat 85,86 . Hence, transient hyperthermic damage to cellular homeostatic mechanisms that permit increased cellular or nuclear membrane permeability to doxorubicin and increased intracellular accumulation could be partly responsible 87,88 .…”