5105

Cooper and co-workers have recently reported that clofarabine added either simultaneously or sequentially increased the metabolism of araC, resulting in synergistic killing of K-562 myeloid leukemia cells [Cancer Chemother Pharmacol. 2004 Oct 16; (Epub ahead of print)]. Studies were conducted to determine if clofarabine would also increase the metabolism of T-araC, a new cytosine analog that has exhibited excellent activity against a broad spectrum of human solid tumor and leukemia/lymphoma xenografts. Initial studies with K-562 leukemia cells showed that the presence of clofarabine inhibited the accumulation of T-araCTP. However, when the clofarabine was removed from the cell culture prior to the addition of T-araC, clofarabine stimulated the phosphorylation of T-araC. A 2-h incubation with clofarabine at 1 μM resulted in a 3-5 fold increase in the metabolism of T-araC (10 μM) 24 h after the removal of the clofarabine. The effect of clofarabine on the metabolism of T-araC was also evaluated in other tumor cell types. Clofarabine stimulated the metabolism of T-araC in K-562 leukemia and HCT-116 colon cells (315 and 300 % of control, respectively), had little effect on the metabolism in MDA-MB-435 breast or RPMI-8226 myeloma cells (145 and 65 % of control, respectively), and inhibited the metabolism in CCRF-CEM T-cell leukemia cells (10% of control). In vivo combination chemotherapy studies were conducted to determine if the modulations observed in vitro were reflective of the in vivo situation. When sc implanted human tumor xenografts were 100-300 mg, clofarabine was administered ip every other day for five treatments (q2d x 5). T-araC was also administered ip q2d x 5 with each treatment occurring the day after each clofarabine treatment. Two models were initially evaluated - CCRF-CEM and K-562 leukemias. Combination treatment of CCRF-CEM leukemia resulted in less than additive activity. T-araC at a dosage of 40 mg/kg/dose elicited a delay in tumor growth (T-C) of 17.2 days; clofarabine at a dosage of 25 mg/kg/dose elicited a T-C value of 7.3 days; and the combination of the two dosages elicited a T-C value of 18.5 days. Combination treatment of K-562 leukemia resulted in greater than additive activity. T-araC at a dosage of 40 mg/kg/dose elicited a T-C value of 34.7 days; clofarabine at a dosage of 25 mg/kg/dose elicited a T-C value of 15.6 days; and the combination of the two dosages elicited a T-C value of >94.9 days with 5/6 long-term survivors (day 120). Since T-araC has a superior preclinical efficacy profile in comparison to araC in human leukemias/lymphomas, these studies provide a rationale for clinical trials using this combination in the treatment of myeloid leukemias. (Supported by NIH grant PO1-CA34200.)

[Proc Amer Assoc Cancer Res, Volume 46, 2005]