Abstract 819: A novel small molecule cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to treatment with gemcitabine

Abstract

RX-3117 (fluorocyclopentenylcytosine) is a novel small-molecule chemotherapeutic agent that belongs to the class of cytotoxic antimetabolite cytidine analogs. Cytidine analogs, including gemcitabine, have been widely used for the treatment of various types of cancer, both hematologic as well as solid. However, despite the success of gemcitabine, there is no oral formulation of gemcitabine and drug resistance is common. Thus, RX-3117 was synthesized as a oral formulation to overcome gemcitabine resistance with a better pharmacologic profile. In this study, the efficacy of RX-3117 was examined in 12 different human tumor (colon, non-small cell lung, small cell lung, pancreatic, renal, ovarian and cervical) xenograft models, grown subcutaneously in athymic nude mice. Not only has RX-3117 demonstrated potent efficacy in several cancer xenograft models but also oral treatment with RX-3117 results in dose-dependent tumor growth inhibition (TGI), even in tumors that are only moderately sensitive or resistant to gemcitabine. In the Colo-205, H460, H69 and CaSki models, gemcitabine treatment resulted in 28%, 14%, 25%, and 0% TGI, respectively, whereas oral treatment with RX-3117 induced 93%, 91%, 62%, and 66% TGI, respectively. This indicates that RX-3117 may have the potential to be used for the treatment of tumors that do not respond to gemcitabine. In order to extend the results established in cell line xenograft models, and to test efficacy in a potentially more clinically relevant system, RX-3117 was evaluated in a single primary low passage human pancreatic Tumorgraft™CTG-0298, which is resistant to gemcitabine and has a favorable RX-3117 activating enzyme profile. Treatment with RX-3117 resulted in dose dependent TGI and was superior to the standard of care agent gemcitabine. This study successfully demonstrated preliminary efficacy and therapeutic potential of RX-3117. Citation Format: Mi Young Yang, Young Bok Lee, Deog Joong Kim, Chang-Ho Ahn, Joel Kaye, Tania Fine, Rina Kashi, Osnat Ohne. A novel small molecule cytidine analog, RX-3117, shows potent efficacy in xenograft models, even in tumors that are resistant to treatment with gemcitabine. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 819. doi:10.1158/1538-7445.AM2014-819

RX-3117 (fluorocyclopentenyl cytosine): a novel specific antimetabolite for selective cancer treatment

“…Yang et al [13] initially tested the efficacy of RX-3117 in nine xenograft models, showing potent activity of the drug in many types of cancer, including gemcitabine-resistant xenografts. Altogether the drug was effective against 17 human colon tumors, human renal cancer, and human pancreatic cancer xenograft models, comparable or better than other analogs or other effective drugs such as paclitaxel.…”

“…It is a novel promising cytidine-analog with a modification on the ribose molecule consisting of a carbon-fluorine bond instead of oxygen and a double bond. It presents interesting features both in bioavailability and pharmacodynamics/efficacy [12,13]. It has an excellent bioavailability compared to other nucleoside analogs, including gemcitabine, and a strong effect on a wide panel of cancer cell lines and xenograft models, including gemcitabineresistant ones [12][13][14].…”

DNA methyltransferases expression in normal tissues and various human cancer cell lines, xenografts and tumors.

“…Twenty-six human tumour xenografts (partially patient-derived, partially from cell lines) were established in nude mice as described earlier. 16 Tumours were maintained subcutaneously in female nude mice (nu/nu) from about 9-10 weeks old either at the Charles Rivers Discovery Research Services (Seattle, WA, USA) or at Champions Oncology (Hackensack, NJ, USA). Both companies comply with the recommendations of the Guide for Care and use of Laboratory Animals, and are accredited by the Association for Assessment and Accreditation of Laboratory Animal Care International.…”

Vitamin E Phosphate Nucleoside Prodrugs: A Platform for Intracellular Delivery of Monophosphorylated Nucleosides

“…This despite a recent report where doses of 120 mg/kg q3d IP were administered in an NCI-H460 xenograft model without evidence of toxicity, albeit typically with a maximum of 4 doses. In this report, NCI-H460 tumors were noted as being insensitive to gemcitabine [ 24 ]. This illustrates the difficulty in administering safe and effective doses of gemcitabine in animal models or humans.…”