Methods and compositions for optimizing blood and tissue stability of camptothecin and other albumin-binding therapeutic compounds

Abstract

The present invention provides methods and formulations for optimizing the anti-cancer and anti-HIV activities of a camptothecin drug, including camptothecin and its related analogs including 9-aminocamptothecin and 9-nitrocamptothecin. The invention involves methodologies and formulations that limit human serum albumin-mediated reduction of the anti-cancer and anti-HIV effects of the camptothecins, and the methods and formulations provide combination therapies in which binding of the camptothecin agent to human serum albumin can be modulated by the administration of a competing agent such as ibuprofen, clofibrate or clofibric acid that also binds human serum albumin. Reduced camptothecin drug binding to human serum albumin can result in elevated camptothecin free drug levels and thus improve the effectiveness of treatment regimens involving these drugs. Further agents such as methotrexate and AZT can also be used in cancer and HIV-positive patients employing camptothecin drugs.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application is a continuation application of U.S. patent application Ser. No. 10 / 101,513, filed Mar. 20, 2002, and the application claims the benefit of U.S. Provisional Application Ser. No. 60 / 276,908, filed Mar. 20, 2001, all of said applications incorporated herein by reference.FIELD OF THE INVENTION[0002]The invention relates in general to methods of optimizing camptothecin and other albumin-binding compounds for therapeutic use, and in particular to a method of using human serum albumin binding compounds to increase the stability and effectiveness in humans of camptothecin compounds and other albumin-binding compounds which have been shown to possess important therapeutic attributes, such as anti-cancer activity, in murine cells or other in vitro studies, but which have been far less successful in humans due to rapid lack of stability in human plasma. In addition, the invention relates to the use of human serum albumin binding c...

AI Technical Summary

Benefits of technology

[0012]It is thus an object of the present invention to utilize human serum albumin binding molecules in a method of achieving increased stability of compounds, such as camptothecin compounds, which have a high affinity for human serum albumin and which are thus generally less effective than optimal when administered in the human bloodstream.

[0013]It is also an object of the present invention to provide therapeutic methods of administering compounds such as camptothecin that have a high affinity for albumin in humans by adding a human serum albumin binding compound with the ability to bind to one or more binding sites on human serum albumin so that the compounds having high affinity for albumin can become more stable when administered and thus are far more effective than therapeutic drugs administered without such additive binding compounds.

Problems solved by technology

Therefore, due to the mechanism of its cytotoxicity, CPT is S-phase specific, indicating that it is only toxic to cells that are undergoing DNA synthesis.

Thus, the overexpression of topo I combined with the faster rate of cell replication provide a limited basis for selectivity via which camptothecins can effect cytoxicity on cancerous cells rather than healthy host tissues.

Unfortunately, under physiological conditions the drug equilibrium favors hydrolysis and, accordingly, the carboxylate form of the camptothecin drug persists.

The labile nature of this alpha-hydroxy lactone pharmacophore has significantly compromised the clinical utility of the camptothecins, as continuous exposures to the active lactone form are requisite for efficacy purposes.

In turn, this effect has negatively impacted the topoisomerase I inhibitory activity of many camptothecins and, by extension, negatively affects their clinical utility.

Ultimately, by modulating the circulatory and tissue levels of free and active camptothecin drug, HSA can negatively impact the anti-cancer efficacy of the camptothecin agent.

The effect of serum albumins on camptothecins also differs markedly between lower vertebrates and humans and this variance has obscured the judicious selection of analogs for advancement to clinical trials.

These interspecies difference have lead to significant anomalies when the data from animal models and clinical studies are compared.

However, no prior methods have recognized or attempted to deal with the problem caused by the human serum albumin binding activity, and thus methods and compositions are needed which can attenuate the negative effects of human serum albumin on the stability of compounds such as camptothecin compounds, e.g., camptothecin or 9-aminocamptothecin, and other compounds or drugs, such as protease inhibitors, which have a high affinity for human serum albumin.

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