Summary Electrochemotherapy (ECT) is a new therapeutic approach combining the effects of a low-permeant cytotoxic drug, bleomycin (BLM), administered i.v. and cell-permeabilizing electric pulses (EPs) locally delivered to tumours. The transient permeabilization of the cell membrane by the EPs allows free access of BLM to its intracellular targets, largely enhancing BLM's cytotoxic effects. ECT efficacy has been proved so far on transplanted subcutaneous murine tumours and on subcutaneous metastases in humans. Here, we present the first study of the effects of ECT on tumours transplanted to livers in rabbits. We used a recently developed EP applicator consisting of an array of parallel and equidistant needles to be inserted in tissues. Effects of EPs alone or of ECT were assessed by histological analysis, tumour growth rates and survival of the treated animals. A transient blood hypoperfusion was seen in the electropulsed areas, with or without BLM, related to EPdependent vasoconstriction but this had no major effects on cell survival. Long-term effects depended on the presence of BLM at the time of EP delivery. Almost complete tumour necrosis was observed after ECT, resulting from both BLM direct cytotoxic effects on electropermeabilized tumour cells and indirect effects on the tumour vessels. A large reduction in tumour growth rate and significantly longer survival times were scored in comparison with control rabbits. Moreover, ECT of liver tumours was well tolerated and devoid of systemic side-effects.When ECT was associated with a local interleukin 2-based immunotherapy, increased local anti-tumour effectiveness as well as a large decrease in the number of metastases were observed. Thus, ECT could become a novel treatment modality for liver tumours and other solid internal malignancies.Keywords: electrochemotherapy; bleomycin; electric pulse; liver tumour; immunotherapy; interleukin 2 Bleomycin (BLM), a non-permeant cytotoxic drug largely used in clinical oncology (Sikic, 1988;Mir et al, 1996), is a relatively large hydrophilic molecule that is carried into the cells by a lowefficiency mechanism . Consequently, very small amounts of BLM enter intact cells, limiting its cytotoxic effects (Orlowski et al, 1988;Poddevin et al, 1991). Brief and intense electric pulses (EPs) delivered in vitro or in vivo are known to induce changes in the plasma membrane of the pulsed cells, resulting in a transient and reversible cell permeabilization (Chang et al, 1992;Orlowski and Mir, 1993). One of the most innovative and promising biomedical applications of electropermeabilization is the therapeutic use of this technique to incorporate cytotoxic drugs into tumour cells (Mir et al, 1995a). In vitro cell electropermeabilization enhances BLM influx into electropulsed cells and thus greatly potentiates BLM cytotoxicity (Orlowski et al, 1988;Poddevin et al, 1991). Furthermore, in vivo experiments on tumour-bearing mice demonstrated that BLM potent anti-tumour effects were obtained by delivering transcutaneous EPs to subcutaneous t...
The tetrapeptide Acetyl-N-Ser-Asp-Lys-Pro (AcSDKP or Goralatide), a physiological regulator of hematopoiesis, inhibits the entry into the S-phase of murine and human hematopoietic stem cells. It has been shown to reduce the damage to specific compartments in the bone marrow resulting from treatment with chemotherapeutic agents, ionizing radiations, hyperthermy, or phototherapy. The present study was performed to assess the therapeutic potential of AcSDKP in vivo in reducing both the toxicity and the hematopoietic damage induced by fractionated administration of doxorubicin (DOX), a widely used anticancer drug. Here we showed that AcSDKP could reduce DOX-induced mortality in mice and could protect particularly the long-term reconstituting cells (LTRCs) in addition to colony forming units-spleen, high proliferative potential colony-forming cells, and colony-forming units–granulocyte-macrophage (CFU-GM) from DOX toxicity. The protection against DOX-induced mortality in mice was improved when AcSDKP was administered for 3 days, at a dose of 2.4 μg/d, by continuous subcutaneous (SC) infusion or fractionated SC injections starting 48 hours before DOX treatment. Moreover, the recovery of the CFU-GM population in the AcSDKP-DOX–treated mice was optimized by the subsequent administration of granulocyte colony-stimulating factor (G-CSF). The coadministration of AcSDKP with DOX may improve its therapeutic index by reducing both acute hematotoxicity on late stem cells and progenitors and long-term toxicity on LTRCs. Optimization of these treatments combined with G-CSF may provide an additional approach to facilitate hematopoietic recovery after cancer chemotherapy.
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