OSI pharmaceuticals report on the pharmacokinetics, safety and efficacy of their anticancer thymidylate synthase inhibitor, OSI-7904L

OSI pharmaceuticals report on the pharmacokinetics, safety and efficacy of their anticancer thymidylate synthase inhibitor, OSI-7904L

DailyUpdates 11th March 2004. According to WHO, there are some 130 million diagnosed diabetics in the world and although modern diabetes drugs have succeeded in treating the symptoms of diabetes, diabetic complication including nephropathies and neuropathies remain a problem. Flinders Medical Centre researchers have made a breakthrough, identifying the cause of one particular neuropathy that leads to gastrointestinal dysfunction.

Cancers of the colon and rectum remain responsible for 56,000 deaths every year in the US, second only to lung cancer. Surgery remains the main form of treatment and is often the only treatment used in early-stage disease. Current surgical practices can however cure only 40%-50% of early-stage cases.

The global colorectal cancer market was estimated to be worth approximately US$1 billion in 2001, of which 60% of the revenues were derived from the US. The market has been predicted to rise further to US$2.5-3 billion within a five-year period. Camptosar™ (Pharmacia Corp.) currently dominates the US colorectal cancer market, but severe diarrhea as a side effect is a clear drawback for this drug (for a full analysis of therapeutic and market opportunities for colon cancer click here). Side effects limit the therapeutic index of many anticancer agents and in an attempt to improve this situation considerable effort has been placed on drug delivery technologies such as liposomal formulations.

The oncology company OSI pharmaceuticals is one player that is exploiting liposomal drug delivery to improve anticancer agents. In particular OSI pharmaceuticals are developing OSI-7904L, a liposomal formulation of the thymidylate synthase inhibitor OSI-7904.

In their recent Journal of Pharmacology & Experimental Therapeutics journal article Dan Drolet and colleagues from OSI pharmaceuticals have published new data describing the enhanced therapeutic index and dose schedule convenience of OSI-7904L compared to OSI-7904. In particular this study was conducted to determine the antitumor efficacy, distribution, pharmacokinetics and safety of OSI-7904L in mice.

In a human colon adenocarcinoma xenograft model in mice, OSI-7904L demonstrated superior anti-tumor efficacy as compared to OSI-7904 or 5-flourouracil. Furthermore, OSI-7904L could be administered less frequently than OSI-7904 while still generating greater tumor growth inhibition. Distribution studies confirmed that OSI-7904L-treated animals had much greater plasma, tissue, and tumor exposure than did OSI-7904 treated animals. Tumor exposures in OSI-7904L-treated mice were increased over 100-fold compared to tumor exposures in OSI-7904-treated mice. Plasma exposures following OSI-7904L administration were greater than dose proportional, consistent with saturation of plasma clearance mechanisms.

These data clearly demonstrated that in mice, OSI-7904L has an increased plasma residence time as well as increased tissue and tumor exposure in comparison to OSI-7904, thus resulting in increased potency. Potential benefits of OSI-7904L include improved efficacy and a more convenient schedule of administration.

Of the 29 different human tumor lines in tumor xenograft cell lines test, colon-derived lines demonstrated the highest inhibitory response activity to OSI-7904L exposure. However, tumor xenograft models of alternate origin were also highly sensitive to OSI-7904L suggesting its role in the treatment of various solid tumors. Indeed, in October 2003--OSI Pharmaceuticals announced that it has initiated a Phase II clinical study of OSI-7904L in patients with previously untreated advanced gastric cancer.

(source DailyUpdates 11th March; for a full abstract of the original paper see J Pharmacol Exp Ther. 2004 Feb 24)

In this edition of DailyUpdates, LeadDiscovery also highlights a role for neuronal insulin resistance in neurodegenerative diseases...the design, synthesis and evaluation of novel hydroxyamides as orally available anticonvulsants...a series of potent and highly selective glycogen synthase kinase-3beta (GSK-3beta) inhibitors...a phase I study investigating vaccination of breast cancer patients with p53-peptide-pulsed dendritic cells...and much more.

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