The anticancer activity of 5’-sulfamoyl-purines in cell culture has been previously reported, but there are no published investigations of activity in vivo. One of the earliest members of this class, 5’-O-aminosulfonyl-adenosine, NSC133114, was reported to have 200nM IC50 in L1210 cells (A.Bloch, Biochemistry 10:4394, 1971). We found the average GI50 for NSC133114 was 10 nM across the full NCI-60 cell line panel. When tested in vivo, NSC 133114 was active in the NCI hollow fiber assay, with an overall score of 28 (maximum possible score is 96). NSC750854, the 6-desamino derivative of NSC133114, also had an average GI50 of 10 nM in the NCI-60 panel, but it was nearly twice as active in vivo as NSC133114, with a hollow fiber score of 52. Thus, NSC750854 was chosen for more extensive testing in a set of 8 distinct xenografts.

The A498 human renal tumor was the most sensitive xenograft, responding to NSC 750854 via the PO, IP and IV routes. Complete regressions of tumors and tumor-free animals at the end of the study were produced by NSC750854 when administered IP once daily at 5 mg/kg for 2 cycles of 5 days or 3.75 mg/kg twice daily (BID) for 2 cycles of 5 days. At an oral dose of 5 mg/kg given BID for 2 cycles of 6-10 doses each, NSC 750854 produced A498 tumor stasis in the absence of body weight loss. Administered IV at 6.4 mg/kg every other day for 2 cycles of 5 doses or 3.2 mg/kg BID every other day for 2 cycles of 10 doses, NSC 750854 also produced tumor regressions, but no tumor free animals at the end of the study.

RPMI-8226 myeloma was the xenograft with the next most sensitive response to NSC750854, with durable tumor stasis following administration by all 3 routes. NSC750854 produced tumor stasis and some regressions in the U251 CNS tumor xenograft, but they were more transient. The PC-3 prostate and LOX melanoma xenografts were responsive to NSC750854 with tumor growth stasis of varying durations. NSC 750854 was effective by all 3 routes of administration but the most dramatic activity was noted with the IP dose route. Among the 8 models tested, the least responsive tumors under the conditions evaluated were Colo 205 colon, HCT-15 colon and UACC-62 melanoma. NSC750854 produced tumor growth suppression but no durable tumor stasis in these 3 models.

These patterns of activity in vitro and in vivo for NSC750854 are substantially different than the patterns observed for the anticancer purines that are approved for clinical use. Ongoing studies with NSC 750854 include determinations of activity in advanced tumors, pediatric human tumor models, pharmacologic behavior, toxicologic profile in additional species, and mechanisms of action.

This work was conducted under an approved IACUC protocol in AAALACi accredited facilities and supported by federal funds from the National Cancer Institute, NIH, under Contract No. HHSN261200800001E.

Citation Format: Melinda G. Hollingshead, Michelle Gottholm-Ahalt, Howard Stotler, John Carter, Cheryl Domitrovich, Adrienne Horner, Jerry M. Collins. 5’-Sulfamoyl purines are highly active in many xenografts of human solid tumors via oral, intravenous, and intraperitoneal routes of delivery. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4489. doi:10.1158/1538-7445.AM2013-4489