Enhancement of the in vivo antitumor activity of clofarabine by 1-beta-D-[4-thio-arabinofuranosyl]-cytosine.

PURPOSE: Clofarabine increases the activation of 1-beta-D-arabinofuranosyl cytosine (araC) in tumor cells, and combination of these two drugs has been shown to result in good clinical activity against various hematologic malignancies. 1-beta-D-[4-thio-arabinofuranosyl] cytosine (T-araC) is a new cytosine analog that has exhibited excellent activity against a broad spectrum of human solid tumors and leukemia/lymphoma xenografts in mice and is currently being evaluated in patients as a new drug for the treatment of cancer. Since T-araC has a vastly superior preclinical efficacy profile in comparison to araC, we have initiated studies to determine the potential value of clofarabine/T-araC combination therapy. METHODS: In vitro studies have been conducted to determine the effect of clofarabine on the metabolism of T-araC, and in vivo studies have been conducted to determine the effect of the clofarabine/T-araC combination on five human tumor xenografts in mice. RESULTS: Initial studies with various tumor cells in culture indicated that a 2-h incubation with clofarabine enhanced the metabolism of T-araC 24 h after its removal by threefold in three tumor cell types (HCT-116 colon, K562 leukemia, and RL lymphoma) and by 1.5-fold in two other tumor cell types (MDA-MB-435 breast (melanoma), and HL-60 leukemia). Pretreatment with clofarabine resulted in a slight decrease in metabolism of T-araC in RPMI-8226 myeloma cells (65% of control) and inhibited metabolism of T-araC in CCRF-CEM leukemia cells by 90%. In vivo combination studies were conducted with various human tumor xenografts to determine whether or not the modulations observed in vitro were reflective of the in vivo situation. Clofarabine and T-araC were administered on alternate days for five treatments each (q2dx5) with the administration of T-araC 24 h after each clofarabine treatment. Combination treatment of HCT-116, K562, HL-60, or RL tumors with clofarabine and T-araC resulted in dramatically superior anti-tumor activity than treatment with either agent alone, whereas this combination resulted in antagonism in CCRF-CEM tumors. The in vivo antitumor activity of clofarabine plus T-araC against HCT-116 tumors was much better than the activity seen with clofarabine plus araC. CONCLUSIONS: These studies provide a rationale for clinical trials using this combination in the treatment of acute leukemias as well as solid tumors and suggest that this combination would exhibit greater antitumor activity than that of clofarabine plus araC.

Preclinical antitumor activity of 4'-thio-beta-D-arabinofuranosylcytosine (4'-thio-ara-C).

PURPOSE: 4'-Thio-beta -d-arabinofuranosylcytosine (4'-thio-ara-C), which has shown significant cytotoxicity against a panel of human tumor lines, was evaluated for antitumor activity against a spectrum of human tumor systems in mice. METHODS: Antitumor activity was evaluated in 15 subcutaneously implanted human tumor xenografts. 4'-Thio-ara-C was administered intraperitoneally using either q1dx9 (daily treatment for nine consecutive days) or q4hx3/q1dx9 (three treatments each day separated by 4-h intervals for nine consecutive days). RESULTS: 4'-Thio-ara-C exhibited an excellent spectrum of activity. Treatment with the compound was curative against HCT-116 colon, SW-620 colon, NCI-H23 NSCL, and CAKI-1 renal tumors and resulted in partial/complete regressions in the DLD-1 colon, NCI-H522 NSCL, DU-145 prostate, and PANC-1 pancreatic tumor models. Tumor stasis was noted for HT29 colon and NCI-H460 NSCL tumors. Tumor inhibition was observed for A549 NSCL, PC-3 prostate, LNCAP prostate, and MDA-MB-435 breast tumors. Of the 15 tumors examined, only CFPAC-1 pancreatic was unresponsive to the compound. In contrast, 1-beta -d-arabinofuranosylcytosine was minimally active at best against CAKI-1 renal, HCT-116 colon, NCI-H460 NSCL, and SW-620 colon tumors. Schedule- and route-dependency studies were conducted using the NCI-H460 NSCL tumor. The activity of 4'-thio-ara-C was independent of schedule when comparing q2dx5 (every other day for five treatments), q1dx9, and q4hx3/q1dx9 treatment schedules. 4'-Thio-ara-C was equally effective by the intravenous and intraperitoneal routes of administration, with the oral route being less efficacious. CONCLUSIONS: On the basis of these results, 4'-thio-ara-C appears to have a profile distinct from other nucleoside antitumor agents and is being advanced to clinical trials.