This metabolic activity of melanoma check details cells triggers arrest and accumulation of cells in
the G1 phase . FACS analyses of the HTB140 cells did not show a major accumulation of cells in G2/M phase 7 days after irradiation, confirming that these cells are among very radioresistant lines, as it was already reported for the viability and survival . Conclusion To improve single effects of protons, FM or DTIC on the inactivation of HTB140 melanoma cells, combined treatments with these agents have been investigated. After being irradiated with protons cells were exposed to either FM or DTIC. The combination of protons and FM did not improve the cell inactivation level achieved by each single treatment. The poor efficiency of the single DTIC treatment was overcome when DTIC was introduced following proton irradiation, giving better inhibitory effects with respect to the single treatments. The molecular mechanisms activated by protons enabled DTIC to express its cytostatic nature. However,
under the studied experimental conditions the level of sensitivity of the HTB140 cells to protons, FM or DTIC remained within 50% of cell inactivation also after their combined application. Acknowledgements This work was supported by the Ministry of Science and Technological Development of Serbia (grants 143044 and 141038) and Istituto Nazionale di Fisica Nucleare, Laboratori Nazionali del Sud, Italy. References 1. MacKie RM: Malignant melanoma: clinical variants and prognostic indicators. Clin Exp Dermatol 2000, 25: 471–475.CrossRefPubMed 2. Daponte A, Ascierto PA, Gravina A, Melucci MT, Palmieri Luminespib G, Comella RAS p21 protein activator 1 P, Cellerino R, DeLena M, Marini G, Comella G: Cisplatin, dacarbazine, and fotemustine plus interferon alpha in patients with advanced malignant melanoma. A multicenter phase II study of the mTOR inhibitor Italian Cooperative Oncology Group. Cancer 2000, 89: 2630–2636.CrossRefPubMed 3. Passagne I, Evrard A, Winum JY, Depeille P, Cuq P, Montero JL, Cupissol D, Vian L: Cytotoxicity, DNA damage, and apoptosis induced by new fotemustine analogs on human
melanoma cells in relation to O6-methylguanine DNA-methyltransferase expression. J Pharmacol Exp Ther 2003, 307: 816–823.CrossRefPubMed 4. Kroes RA, Abravaya K, Seidenfeld J, Morimoto RI: Selective activation of human heat shock gene transcription by nitrosourea antitumor drugs mediated by isocyanate-induced damage and activation of heat shock transcription factor. Proc Natl Acad Sci USA 1991, 88: 4825–4829.CrossRefPubMed 5. Grossman D, Altieri DC: Drug resistance in melanoma: mechanisms, apoptosis, and new potential therapeutic targets. Cancer Metastasis Rev 2001, 20: 3–11.CrossRefPubMed 6. Jungnelius U, Ringborg U, Aamdal S, Mattsson J, Stierner U, Ingvar C, Malmstrom P, Andersson R, Karlsson M, Willman K, et al.: Dacarbazine-vindesine versus dacarbazine-vindesine-cisplatin in disseminated malignant melanoma. A randomised phase III trial. Eur J Cancer 1998, 34: 1368–1374.CrossRefPubMed 7.