Role of heat treatment in childhood cancers: distinct resistance profiles of solid tumor cell lines towards combined thermochemotherapy.
BACKGROUND
Since information on the efficacy of hyperthermia in combination with chemotherapy on pediatric tumors is limited, we performed a systematic analysis on the synergistic effects of a combined application of heat and chemotherapy on 20 tumor cell lines derived from patients with neuroblastomas, Ewing tumors, germ cell tumors (GCT), and osteosarcomas.


METHODS
Cisplatin (cDDP), a cross-linking agent, and etoposide (VP-16), a topoisomerase II inhibitor, were examined either alone or in combination with heat (42 degrees C, 43 degrees C) by using the XTT-assay 1.


RESULTS
Our data demonstrate that heat stress at 43 degrees C for 1 hr, but not at 42 degrees C, leads to a notable cytotoxic effect on the different tumor cells. The comparison of mean survival fractions reveals values between 62% for neuroblastoma cells and 76% for Ewing tumor cells. Analyzing the sensitivity to chemotherapy alone, our results show that cDDP (5 microg/ml) reduces cell growth to 47% in Ewing tumor cells, to 61% in neuroblastoma cells, to 75% in GCT cells, and to 76% in osteosarcoma cells. Treatment with VP-16 (10 microg/ml) decreases cell survival to mean values between 58% (neuroblastomas) and 77% (osteosarcomas). Simultaneous application of heat and chemotherapy enhances synergistically cDDP cytotoxicity in all tumor types tested, whereas the efficacy of VP-16 is only slightly influenced by additional application of hyperthermia. The cytotoxicity of cDDP (5 microg/ml) can be increased by a factor of between 1.5 and 2.5 at 42 degrees C and from 2.6 to 14.0 at 43 degrees C. Furthermore, the results show that the sensitivity to heat (43 degrees C) as well as the sensitivity to chemotherapy and combined thermochemotherapy varies considerably between cell lines of the same tumor group.


CONCLUSIONS
Simultaneous application of hyperthermia synergistically enhances the cytotoxicity of the alkylating agent cDDP, but not of the topoisomerase II inhibitor VP-16, in a defined spectrum of cell lines from different pediatric tumor entities.
Debes
Anette
A
Clinic of Pediatric Oncology, Hematology and Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
Willers
Reinhart
R
Göbel
Ulrich
U
Wessalowski
Rüdiger
R
D000970:Antineoplastic Agents / Q000494:pharmacology*; D001859:Bone Neoplasms / Q000473:pathology*; D002455:Cell Division; D045744:Cell Line, Tumor / Q000187:drug effects / Q000473:pathology*; D002470:Cell Survival; D002648:Child; D002945:Cisplatin / Q000494:pharmacology; D003131:Combined Modality Therapy; D003432:Cross-Linking Reagents / Q000494:pharmacology; D005047:Etoposide / Q000494:pharmacology; D006801:Humans; D006979:Hyperthermia, Induced; D009373:Neoplasms, Germ Cell and Embryonal / Q000473:pathology*; D009447:Neuroblastoma / Q000473:pathology*; D059005:Topoisomerase II Inhibitors
D000970:Antineoplastic Agents; D003432:Cross-Linking Reagents; D059005:Topoisomerase II Inhibitors; D005047:Etoposide; D002945:Cisplatin