The goal of this project is the discovery and development of new anticancer agents with solid tumor activity from leads obtained from plants. The need for this is significant given the paucity of anticancer agents active against the major solid tumors of man. During the past 5 years, nearly 4000 crude plant extracts, from the laboratory of Dr. Joseph Hoffmann at the University of Arizona, have been evaluated for solid tumor selectivity by Dr. Fred Valeriote, now at the Josephine Ford Cancer Center. The results of these studies have provided this project with 30 prioritized, primary hits to continue with isolation (through bioassay-directed fractionation) and identification of the active compound(s) from these plants over the next 5 years In order to accomplish the objectives, bulk collections will be made as needed or plants will be grown in experimental field plots to provide sufficient material for expanded testing both in vitro and in vivo. Additional material will be generated through aeroponic/hydroponic systems, especially when root material is the primary source of the active compound(s). Also, 200 new plants will be collected each year with the new and old leads prioritized annually. Six priority plants will be targeted for completion each year to generate at least 6 active compounds for both in vitro and in vivo testing. Greater emphasis will be placed on novel compounds over known compounds with either new or known anticancer activity. The anticancer drug development component will be carried out at the Josephine Ford Cancer Center. The pure compound moves into formulation, pharmacology and therapeutic assessment. There are three essential components to in vivo pharmacology: testing development of analytical methods for chemical analysis of the new compounds, development of a suitable IV formulation through biopharmaceutical measures, and preliminary pharmacology testing for drug clearance and distribution. Doses and target drug concentrations will be established in vitro. Mice will bear bilateral tumors that have grown to 100 to 300 mm3 prior to initiation of dosing. Doses of each agent contained in 0.2 ml volume for parenteral administration will be estimated from traditional dosage demands and dosages adjusted for in vitro pharmacology results. The methodology for the study on therapeutic efficacy to test doses of compound, up to the maximum tolerated dose, in tumor bearing mice (syngeneic with a murine tumor or xenografted wit.
|Choi, Hyukjae; Mevers, Emily; Byrum, Tara et al. (2012) Lyngbyabellins K-N from Two Palmyra Atoll Collections of the Marine Cyanobacterium Moorea bouillonii. European J Org Chem 2012:5141-5150|
|Gao, Song; Xu, Ya-ming; Valeriote, Frederick A et al. (2011) Pierreiones A-D, solid tumor selective pyranoisoflavones and other cytotoxic constituents from Antheroporum pierrei. J Nat Prod 74:852-6|