Lovastatin, a drug successfully used in the clinic to prevent and to treat coronary heart disease, has recently been reported to decrease the incidence of melanoma in lovastatintreated patients. Lovastatin has also been proved to potentiate antitumor effects of both cisplatin and TNF-␣ in murine melanoma models. Recently, an augmented therapeutic effect of lovastatin and doxorubicin has been reported in 3 tumor models in mice. In our preliminary study lovastatin caused retardation of melanoma growth in mice treated with doxorubicin (Feleszko et al. J Natl Cancer Inst 1998;90:247-8). In the present report, we supplement our preliminary observations and demonstrate in 2 murine and 2 human melanoma cell lines that lovastatin effectively potentiates the cytostatic/cytotoxic activity of doxorubicin in vitro via an augmentation of apoptosis (estimated with PARP-cleavage assay, annexin V assay and TUNEL) . The combined antiproliferative activity of lovastatin and doxorubicin was evaluated using the combination index (CI) method of Chou and Talalay, revealing synergistic interactions in melanoma cells exposed to lovastatin and doxorubicin. In B16F10 murine melanoma model in vivo, we have demonstrated significantly increased sensitivity to the combined treatment with both lovastatin (5 mg/kg for 14 days) and doxorubicin (4 ؋ 1 mg/kg) as compared with either agent acting alone. Lovastatin treatment resulted also in significant reduction of the number of experimental metastasis in doxorubicin-treated mice. The results of our studies suggest that lovastatin may enhance the effectiveness of chemotherapeutic agents in the treatment of malignant melanomas.

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Angiogenesis, the growth of new blood vessels from a preexisting microvascular bed, is of crucial importance for the growth, maintenance, and metastasis of solid tumors. Various anti-angiogenic factors are currently being investigated, indicating that angiogenesis may soon become a suitable target for novel antitumor therapies. However, most of the currently available potent angiostatic factors (angiostatin, endostatin) are small protein fragments and their clinical application may be associated with an unusual cost expense. In their recent report Vincent and colleagues [1] demonstrate an interesting, anti-angiogenic activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor (HMG-CoA RI), cerivastatin. Inhibitors of HMG-CoA reductase (or statins) represent a newly discovered family of chemically related molecules, selected for their lipid-lowering e¡ect. Statins are extensively used in medical practice, and large clinical trials have demonstrated that this class of lipid-lowering drugs greatly reduces cardiovascular-related morbidity and mortality in patients with and without coronary disease ([2]; for review see [3]). According to recent studies, the bene¢cial e¡ect of statins may also be attributed to their favorable e¡ects on vasculature [3].In fact, we have demonstrated for the ¢rst time that lovastatin, another HMG-CoA RI, inhibits angiogenesis, and this e¡ect was due to the decreased production of VEGF imposed by lovastatin in tumor cells [4]. Interestingly, the results of our study and the recent paper of Vincent et al. do not match that of Kureishi et al. [5], who show that statins promote angiogenesis. This discrepancy most likely depends of the type of the examined cells and the di¡erence of the experimental model used. In our study, lovastatin e¡ectively suppressed VEGF production by tumor cells harboring ras mutations. This resulted in the inhibition of bloodvessel formation, and ¢nally in the retardation of tumor growth. These results suggest statin's remarkable anti-angiogenic and antitumor e¡ects, particularly towards tumors harboring ras mutations.Until recently, the bene¢cial antitumor e¡ects of treatment with statins have been attributed only to their direct antiproliferative e¡ects on tumor cells. Evidence was provided that statins induce cell cycle block in the G 1 phase, interfere with the function of the Ras oncoprotein, and induce a potent apoptotic response. Some of the statins are being tested in clinical trials as potential novel antitumor agents, as they have been widely used and have well-de¢ned pharmacokinetics at the clinical level, displaying negligible adverse side e¡ects. Strikingly, a large clinical trial with lovastatin (a total of 6605 patients), designed to study prevention of acute coronary events with lovastatin, demonstrates a signi¢cant reduction in the incidence of melanoma among lovastatintreated patients [2].The results of our previous study [4] and the paper of Vincent et al. [1] underline the feasibility of utilizing statins as anti-angiogenic agents in tu...