Abstract 3839: Comparison of thio-deoxy-cytidine (TdCyd) and aza-thio-deoxy-cytidine (Aza-TdCyd) in solid and liquid tumor cell lines and PPTC pediatric xenografts
Authors: Teicher Beverly A. , Lock Richard B. , Evans Kathryn , Houghton Peter J. , Kurmasheva Raushan T. , Gorlicki Richard , Erickson Steve , Wishka Donn , Morris Joel , Difilippantonio Michael , Collins Jerry E. , Smith Malcolm A. , Doroshow James H. 
Published: August 2019

Abstract
Cytidine analogs target DNA methyltransferases as at least one of their mechanisms of action. The mechanism(s) of action of these compounds are incompletely elucidated and vary. TdCyd and Aza-TdCyd are thio-nucleoside analogs of cytidine which differ by a single nitrogen atom in the cytidine ring. Here the activity in solid and liquid tumor cell lines, and pediatric tumor xenografts is compared.
Methods: Cytotoxicity was examined after 2, 3 and 7-day exposure in 10 solid tumor lines and 6 liquid tumor lines. TdCyd was administered (1mg/kg) ip, daily for 5 days for 4 weeks (total 20 doses). Aza-TdCyd was administered (1.5, 1.0 or 0.5 mg/kg) ip, daily for 5 days for 4 weeks (total 20 doses). For solid tumors (sc), events were defined as 4X increase in tumor volume from day 0, for acute lymphoblastic leukemias (ALL) as %hCD45 cells exceeding 25%. The Kaplan-Meier method was used to compare time-to-event across treated and control groups. The objective response categories are progressive disease (PD), stable disease (SD), partial response (PR), complete response (CR), and maintained complete response (MCR) [Pediatr Blood Cancer 2007;49:928-40].
Results: Aza-TdCyd was, in general, a more active antitumor agent than TdCyd. In cell culture, after 7-days exposure Aza-TdCyd was 3-to 4-fold more potent than TdCyd in 10 solid tumor lines (IC50 1.2 vs 3.7 uM) and similarly more potent in 6 liquid tumor lines (0.03 vs 0.11 uM). TdCyd and Aza-TdCyd were tested in Ewing sarcoma, rhabdoid tumor, rhabdomyosarcoma, osteosarcoma, and pediatric acute lymphoblastic leukemia (ALL) patient-derived xenografts. The sarcomas were implanted subcutaneously, and the leukemias were implanted intravenously. At tolerable doses, the anticancer activity of both TdCyd and Aza-TdCyd were modest in the Ewing sarcoma (4) and rhabdomyosarcoma (4) models. The activity of both compounds was also modest in 5 out of 6 osteosarcoma models. However, the median survival of mice bearing the OS-9 osteosarcoma doubled (42 days) upon treatment with TdCyd and increased nearly 4-fold (84 days) in mice treated with Aza-TdCyd. While TdCyd had modest ALL activity, Aza-TdCyd increased median survival from 9.1(2-16) days in controls to &gt;70 in 7/9 ALL models. Aza-TdCyd antileukemic activity was maintained at lower doses of the agent with median survivals of 75.4 days at 1.5mg/kg, 72.7 days at 1.0 mg/kg and 62.0 days at 0.5 mg/kg. Both TdCyd (NCT02423057) and Aza-TdCyd (NCT03366116) are in phase 1 clinical testing. Supported by NCI Grants: CA199222, CA199221, CA199297, CA199288, CA199000 and NCI Contract No. HHSN261200800001E.
Citation Format: Beverly A. Teicher, Richard B. Lock, Kathryn Evans, Peter J. Houghton, Raushan T. Kurmasheva, Richard Gorlicki, Steve Erickson, Donn Wishka, Joel Morris, Michael Difilippantonio, Jerry E. Collins, Malcolm A. Smith, James H. Doroshow. Comparison of thio-deoxy-cytidine (TdCyd) and aza-thio-deoxy-cytidine (Aza-TdCyd) in solid and liquid tumor cell lines and PPTC pediatric xenografts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3839.