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Letters to the Editor

Department of Immunology and Department of Pediatric Pneumonology, Allergic Diseases and Hematology; The Medical University Children’s Hospital; Dzialdowska 1; PL-01-184 Warszawa, Poland; Marek Jakóbisiak; Department of Immunology, Institute of Biostructure, The Medical University of Warsaw, Chalubiskiego 5; PL-02-004 Warszawa, Poland

Correspondence re: B. Agarwal et al., Lovastatin Augments Apoptosis Induced by Chemotherapeutic Agents in Colon Cancer Cells. Clin. Cancer Res., 5: 2223–2229, 1999.

We read with great interest the article by Agarwal et al. (1) . It shows that lovastatin was able to augment apoptosis induced by 5-fluorouracil or cisplatin in colon cancer cells. The authors suggest that lovastatin may potentially be used in chemotherapy for colon cancers. We think that lovastatin or other statins could potentially be used in combination therapy for other tumors as well. In fact, in our recent study, we have demonstrated for the first time that lovastatin augments both the in vitro and in vivo antitumor effects of cisplatin in a murine melanoma model (2) . Lovastatin was also found to potentiate the antitumor activity of doxorubicin in three murine tumor models, including colon and lung carcinoma models.¹ What is still more interesting from a clinical point of view is that potentiation of antitumor effects in this study was accompanied by attenuation of doxorubicin-induced cardiotoxicity. It is also worth mentioning that lovastatin is able to augment the antitumor activity of tumor necrosis factor (3) .

Thus, the application of lovastatin, which was introduced in the clinic to treat hypercholesterolemia, may not be confined only to the prevention and treatment of coronary heart disease. One cannot dismiss the possibility that it will eventually extend to include supplementation of tumor therapy, particularly in elderly patients also suffering from coronary heart disease, who constitute the main group of statin consumers (4) . In these patients, lovastatin could serve two purposes: (a) to lower blood cholesterol levels; and (b) to strengthen the effectiveness of tumor chemotherapy. It could also attenuate the toxic side effects of chemotherapeutics, both directly (at least in the case of doxorubicin) and indirectly by reducing the doses necessary to achieve the antitumor effects. Because aging patients progressively predominate among cancer patients, we should remember that they are more vulnerable to the adverse effects of chemotherapy (5) .

Agarwal, B., Bhendwal, S., Halmos, B., Moss, S. F., Ramey, W. G., and Holt, P. R. Lovastatin augments apoptosis induced by chemotherapeutic agents in colon cancer cells. Clin. Cancer Res., 5: 2223–2229, 1999.

Feleszko, W., Zagodon, R., Gob, J., and Jakóbisiak, M. Potentiated antitumour effects of cisplatin and lovastatin against MmB16 melanoma in mice. Eur. J. Cancer, 34: 406–411, 1998.

Feleszko, W., Bakowiec, E. Z., Sieberth, E., Marczak, M., Dbrowska, A., Giermasz, A., Czajka, A., and Jakóbisiak, M. Lovastatin and TNF- exhibit potentiated antitumor effects against Ha-ras transformed murine tumor via inhibition of tumor-induced angiogenesis. Int. J. Cancer, 81: 560–567, 1999.

Scandinavian Simvastatin Survival Study Group. Randomised trial of cholesterol lowering in 4444 patients with coronary heart disease: the Scandinavian Simvastatin Survival Study (4S). Lancet, 344: 1383–1389, 1996.

McNeil, C. Greying of America will foster new strategies in oncology. J. Natl. Cancer Inst., 89: 1398–1399, 1997.

Reply

Banke Agarwal: Division of Gastroenterology, St. Luke’s-Roosevelt Hospital Center, New York, New York 10025

Peter R. Holt¹ : Department of Medicine, College of Physicians and Surgeons, Columbia University, New York, New York 10027. We agree with Feleszko et al. that augmentation by lovastatin of apoptosis induced by chemotherapeutic agents is not unique to colon cancer. Soma et al. (1 , 2) have used simvastatin to augment the antitumor effect of nitrosoureas in gliomas. Morris et al. (3) found that lovastatin augmented apoptosis induced by mitomycin-C in hepatoma cell lines. Lovastatin also induces apoptosis in acute myeloid leukemia cells (4 , 5) . Furthermore, cancer cells with mutated k-ras are relatively resistant to chemotherapy- and radiation-induced apoptosis, and lovastatin restores the sensitivity to apoptosis in these cells (6 , 7) . Newman et al. (4) have shown that simvastatin [another hydroxymethylglutaryl coenzyme A (HMG-CoA) reductase inhibitor] selectively targets leukemic cells while sparing the normal bone marrow progenitors. Thus, lovastatin could make tumor cells more sensitive to apoptosis while sparing the normal cells, thereby potentially increasing tumor cell kill and reducing the adverse effects of chemotherapeutic regimens/radiotherapy regimens. Combination of lovastatin or other HMG-CoA reductase inhibitors in conjunction with standard chemotherapeutic agents/radiotherapy should therefore be evaluated for potential improvement of outcomes in management of several cancers including colon cancers.

FOOTNOTES

¹ W. Feleszko, I. Mynarczuk, E. Z. Bakowiec-Iskra, A. Czajka, T. Switaj, T. Stokosa, A. Giermasz, and M. Jakóbisiak. Lovastatin potentiates antitumor activity and attenuates cardiotoxicity of doxorubicin in three tumor models in mice, submitted for publication.

² To whom requests for reprints should be addressed.

Received 11/12/99; accepted 11/22/99.

REFERENCES

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2. Soma M. R., Baetta R., de Renzis R. M., Mazzini G., Devegna C., Magrassi L., Butti G., Pessota S., Paoletti R., Fumagelli R. In vivo enhanced antitumor activity of carmustine by simvastatin. Cancer Res., 55: 597-602, 1995.[Abstract/Free Full Text]
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6. Miller A. C., Kariko K., Myers C. E., Clark E. P., Samid D. Increased radioresistance of EJras-transformed human osteosarcoma cells and its modulation by lovastatin, an inhibitor of p21ras isoprenylation. Int. J. Cancer, 53: 302-307, 1993.[Medline]
7. Miller A. C., Samid D. Tumor resistance to oxidative stress: association with ras oncogene expression and reversal by lovastatin, an inhibitor of p21ras isoprenylation. Int. J. Cancer, 60: 249-254, 1995.[Medline]

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