OSI-7904L [(S)-2-[5-[(1,2-dihydro-3-methyl-1-oxobenzo[f]quinazolin-9-yl)methyl]amino-1-oxo-2-isoindolynl]-
glutaric acid] is a liposomal formulation of the highly specific, noncompetitive,
thymidylate synthase inhibitor OSI-7904 (also known as
GW1843,
1843U89, and GS7904). The
liposome formulation was developed to enhance the therapeutic index and dose schedule convenience of this potent
antifolate compound. The studies presented here were 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 antitumor efficacy compared with OSI-7904 or
5-fluorouracil. Furthermore,
OSI-7904L could be administered less frequently than OSI-7904 although 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, based on area under the curve, in OSI-7904L-treated mice were increased over 100-fold compared with
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.
OSI-7904L was much more toxic than OSI-7904 in the mouse with primary toxicities to the intestines, bone marrow, and thymus. Minimal toxicity to the lungs and liver was noted. These data clearly demonstrated that in mice,
OSI-7904L has an increased plasma residence time as well as increased tissue and
tumor exposure compared with OSI-7904, thus resulting in increased potency and toxicity. Potential benefits of
OSI-7904L include improved efficacy and a more convenient schedule of administration.