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Cytokinetic and Molecular Pharmacology Studies of Arabinosylcytosine in Metastatic Melanoma¹

Department of Developmental Therapeutics [J. S. H., D. H. H., P. S., J. A. G., E. F.], and Department of Biomathematics [S. L. G.], The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, Houston, Texas 77025

Eighteen patients with metastatic melanoma involving the skin were treated with 5-day courses of arabinosylcytosine (ara-C) every 3 weeks. Of the 13 adequately treated patients, there was 1 excellent objective response which lasted for 8 months and 2 transient partial responses. The ara-C kinase [activating enzyme (K)] and ara-C deaminase [inactivating enzyme (D)] were measured prior to treatment. The K values were higher in the responding patients, and the D values were higher in the nonresponding patients. The K/D ratio was significantly higher in the former patients, compared with that in the latter.

Similarly, the proportion of tumor cells in DNA synthesis as determined from labeling indices was highest in the response group. Also, the labeling index percentage was depressed to a greater degree during therapy and remained depressed for a longer period of time after therapy in the patients who responded to treatment, when compared with those who failed to respond. For the nonresponders, recovery of DNA synthesis was complete or nearly complete by Day 21 post therapy.

It is concluded from this study that ara-C is inactive in the majority of patients with melanoma, that it has greater activity in females with melanoma compared to males, and that enzyme and cytokinetic studies can be used to predict clinical response to ara-C.

¹ This work was supported in part by Contract PH 43-66-1156, Chemotherapy, National Cancer Institute, NIH, USPHS, Bethesda, Md.

² To whom requests for reprints should be addressed at the Department of Developmental Therapeutics, The University of Texas M. D. Anderson Hospital and Tumor Institute at Houston, 6723 Bertner Avenue, Houston, Texas 77025.

³ Present address: Department of Internal Medicine, American University Hospital, American University of Beirut, Beirut, Lebanon.

⁴ Present address: Children's Cancer Research Foundation, Inc., 35 Binney Street, Boston, Mass. 02115.

Received 5/19/72. Accepted 9/ 5/72.