Abstract 3521: Alleviation of cancer chemotherapeutic agent-induced toxicity by the synthetic panaxytriol analogues of Panax Ginseng

Abstract

Abstract Therapeutic index (TI) of cancer therapeutic agent is the ratio of maximal tolerated dose (MTD) and the optimal therapeutic dose (OTD). “Reduction in toxicity” and/or “increasing efficacy” by augmentation or synergy will invariably lead to improved TI and patient's well-being during therapy. We found a series of polyacetylene small molecules that is promising just to do that. Through total synthesis, we designed the panaxytriol (PXT) analogs of panax ginseng C.A. Meyer, such as PXTA, PXTAI, PXTAEI and its isomers that are biologically more active than their parent natural ingredient, PXT. At sub-toxic doses, the PXT-compounds, as a single entity (e.g., not an extract, mixture or preparation), are found to process the following intriguing pharmacological properties that have potential applications in cancer chemotherapy or radiation therapy. They are: (i) Exhibited moderate anti-tumor effect in the absence of any toxicity, and slightly augment or synergize anti-tumor effect of taxol or epothilones, in xenograft tumor bearing nude mice; (ii) Significantly or markedly reduced cancer therapeutic agent-induced toxicity such as body-weight losses (e.g., by Taxol, iso-oxazole fludelone, iso-oxazole dehydelone, 5-FU, cyclophosphamide), lethality (e.g., high dose 5-FU) and neurotoxicity (e.g., peripheral neuropathy induced by Taxol); (iii) Showed moderate anti-inflammatory effect in foot-paw-carrangreenan assays in CD-1 mice; (iv) Improved the hematological parameters following high dose 5-FU; (v) The alleviation of body-weight loss also manifested by the oral administration; (vi) Reduced the radiation-induced body-weight loss in CD-1 mice; (vii) Reduced the lethality of radiation; and (viii) Induced the cancer preventive phase II enzyme, quinone reductase (NQ01). PXT-analogs also stimulated human PBMC proliferation in a biphasic and delayed manner in vitro and stimulated splenocyte proliferation of CD-1 mice in delayed manner, suggesting the immuno-enhancing effect. In conclusion, our results demonstrate that co-administration of PXT-based agent with a range of cancer chemotherapeutic agents or radiation therapy will decrease various therapy-associated toxicities and thus increase the therapeutic index. These findings indicate a promising improvement for the cancer chemotherapeutic or radiation therapeutic strategies. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3521. doi:10.1158/1538-7445.AM2011-3521