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Effect of Very High-Dose Thymidine Infusions on Leukemia and Lymphoma Patients^1,4,

Department of Medicine, Developmental Chemotherapy Service and Clinical Pharmacology Laboratory [M. S. B., T. M. W., K. V., M. O., C. W. Y.], Hematology/Lymphoma Service [B. C., M. A.], the Pharmacology Laboratory [T-C. C.], and Department of Pathology [M. A., W. H.], Memorial Sloan-Kettering Cancer Center, New York, New York 10021

The physiological pyrimidine nucleoside thymidine (dThd) is cytotoxic to normal and neoplastic cells in culture that are exposed to concentrations in excess of 1 mM for prolonged periods. In order to explore the antileukemic potential of the compound, we have treated six patients with relapsed leukemia or lymphoma with marrow and blood involvement, by prolonged infusions of dThd, at dosages of 90 to 240 g/sq m/day for 14 to 29 days. Mean plasma dThd concentration ranged from 3.8 to 5.5 mM. Cerebrospinal fluid levels were measured on three occasions and ranged from 2 to 23.5% of simultaneous plasma levels. Diarrhea was dose limiting in one patient. The other side effects included nausea and vomiting in all patients, hepatotoxicity in two patients, electrolyte imbalance in one, progression of a pericardial effusion to tamponade in one, and mild central nervous system toxicity in five. In all cases, this therapy produced bone marrow aplasia. One patient with acute lymphoblastic leukemia, refractory to prior treatment, achieved a complete remission which lasted for 16 weeks. Another patient with lymphoblastic lymphoma had a greater than 50% reduction in his mediastinal mass which lasted for less than 1 month.

At multiple points during therapy, the bone marrow S-phase fraction was measured by flow cytometry and autoradiography. In five patients, the proportion of cells in S phase increased during the first few days of the infusion but then returned to base line, concomitant with an overall reduction in the number of bone marrow blasts.

Cytoreduction was evaluated by the technique of W. Hiddemann, B. D. Clarkson, T. Buchener, M. R. Melamed, and M. Andreeff (Blood, 59: 216–225, 1982). The magnitude of tumor cell kill ranged from 0.7 to 3.6 logs of blasts/cu mm of bone marrow.

The data demonstrate that dThd is able to induce a complete remission in a patient with acute leukemia previously refractory to treatment. However, because of the very large drug quantities, fluid volumes, and the prolonged course required to produce the necessary tumor cell kill, this treatment approach is too impractical to be used extensively.

¹ Supported in part by USPHS Grants CA 05826 and CA 18856 and by Contract CM 97274 from the National Cancer Institute.

⁴ Presented in part at the 71st Annual Meeting of the American Association for Cancer Research, San Diego, CA, May 1980 (3).

² Recipient of partial support from Basic Science Chemotherapy Training Grant T32-CA-09297. To whom requests for reprints should be addressed, at Division of Medical Oncology, J. Graham Brown Cancer Center, University of Louisville, Louisville, KY 40292.

Received 5/10/83. Accepted 1/26/84.

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