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Research Articles: Therapeutics, Targets, and Development

Defining regional infusion treatment strategies for extremity melanoma: comparative analysis of melphalan and temozolomide as regional chemotherapeutic agents

Departments of ¹ Surgery and ² Pathology, Duke University Medical Center, Durham, North Carolina

Requests for reprints: Douglas S. Tyler, Duke University Medical Center, Box 3118, Durham, NC 27710. Phone: 919-684-6858; Fax: 919-681-8701. E-mail: tyler002{at}acpub.duke.edu

Abstract

Five different human melanoma xenografts were used in a xenograft model of extremity melanoma to evaluate the variability of tumor response to regionally administered melphalan or temozolomide and to determine if various components of pertinent drug resistance pathways for melphalan [glutathione S-transferase (GST)/glutathione] and temozolomide [O⁶-alkylguanine DNA alkyltranferase (AGT)/mismatch repair (MMR)] could be predictive of tumor response. Xenograft-bearing rats underwent regional isolated limb infusion with either melphalan (90 mg/kg) or temozolomide (2,000 mg/kg). The levels of AGT activity, GST activity, glutathione level, and GST/AGT expression were examined in this group of xenografts and found to be quite heterogeneous. No correlation was identified between melphalan sensitivity and the GST/glutathione cellular detoxification pathway. In contrast, a strong correlation between the levels of AGT activity and percentage increase in tumor volume on day 30 (r = 0.88) was noted for tumors treated with temozolomide. Regional therapy with temozolomide was more effective when compared with melphalan for the xenograft with the lowest AGT activity, whereas melphalan was more effective than temozolomide in another xenograft that had the highest AGT activity. In three other xenografts, there was no significant difference in response between the two chemotherapy agents. This study shows that AGT activity may be useful in predicting the utility of temozolomide-based regional therapy for advanced extremity melanoma tumors. Our observations also point out the limited ability of analysis of the GST/glutathione pathway to predict response to chemotherapies like melphalan whose resistance is primarily mediated through a complex mechanism of detoxification. [Mol Cancer Ther 2007;6(5):1492–500]

Grant support: Veterans Affairs Merit Review grant (D.S. Tyler), Institute of Genomic Sciences and Policy at Duke University Medical Center grant (D.S. Tyler, F. Ali-Osman, and H.S. Friedman), and American College of Surgeons Oncology Group Correlative Science grant (D.S. Tyler).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Received 11/20/06; revised 2/13/07; accepted 3/23/07.

This article has been cited by other articles:

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