Published in Cancer Detection and Prevention 2000; 24(Supplement 1).

Differential modulation of doxorubicin toxicity by HMBA in malignant mesothelioma cell lines

C Palumbo PhD 1, S Scarpa PhD 2, A Modesti MD 3

1,3 Dept Experimental Medicine and Biochemical Sciences, Tor Vergata University;, 2 Institute of General Pathology, Catholic University; Rome, Italy,

AIM: Malignant mesothelioma is a rare tumor highly refractory to chemotherapy. The primary tumor represents the leading cause of death in mesothelioma patients, which median survival from diagnosis is less than 2 years. Our aim was to investigate the cytotoxic effects of doxorubicin-HMBA combinations on malignant mesothelioma cell lines. HMBA is a differentiating agent, displaying in vitro and in vivo antineoplastic activity, which clinical use is limited by the high serum levels required to achieve therapeutic efficacy. However intrapleural administration might allow to reach local therapeutic levels of HMBA in mesothelioma patients. METHODS: Three human malignant mesothelioma cell lines of different histotype have been used in cytotoxicity assays based on the MTS method. Dose-response curves have been performed for the assessment of the relative doxorubicin chemosensitivity of the cell lines. For combined treatments a dose of doxorubicin corresponding to the IC50 value has been used together with HMBA 5 mM for each cell line. RESULTS: The combined treatments resulted in higher toxicity levels than those obtained with either doxorubicin or HMBA alone. The combined effect analysis revealed that the cytotoxic activity of the two drugs was synergistic in two cell lines, whereas it was less than additive in the third one. CONCLUSIONS: Our results suggest that doxorubicin-HMBA combinations might determine synergistic toxicity in a subset of mesotheliomas and, underlining the importance to characterize the biological determinants of this subset of tumors, encourage to further explore the potential of the doxorubicin-HMBA combined treatment for the therapy of this highly chemoresistent cancer.

KEY WORDS: Combined treatment, Combination Index.

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Paper presented at the International Symposium on Impact of Biotechnology on Cancer Diagnostic & Prognostic Indicators; Geneva, Switzerland; October 28 - 31, 2000; in the section on novel therapies.