Experimental and Clinical Therapeutics

Monday, October 17, 2005 3:00 PM-5:00 PM Exhibit Hall

(PP113) Assessing tumor pH as a determinant of the efficacy weak acid and base chemotherapeutics in-vivo.

Gerweck, Leo*,1, Vijayappa, Shashirekha1, 1 Massachusetts General Hospital, Boston, MA, United States

ABSTRACT- Purpose/Objective: The extracellular pH of tumor tissue is more acidic than the extracellular pH of normal tissue, whereas the intracellular pH is similar in both tissues. This gives rise to a naturally occurring pH gradient difference between these tissues, and provides a potential target for the treatment of cancer. In principle, at decreasing pH, the non-ionized fraction of a weak acid chemotherapeutic increases, allowing it to pass through the non-polar cell membrane and accumulate intracellularly. For a weak base the opposite pertains. pH-gradient dependent drug uptake and cytotoxicity has been confirmed in in-vitro studies. In this study we evaluate the influence of the pH-gradient on drug cytotoxicity in the more complex and dynamic tumor microenvironment. Materials/Methods: The human lung carcinoma 54A was transplanted and evaluated in immune-deficient NCRnu/nu mice. Intravenous glucose was used to selectively reduce extracellular tumor pH without altering intracellular pH. Test mice were administered the weak acid chlorambucil alone or the weak base doxorubicin alone, or following glucose administration. Response was evaluated as the time for treated tumors to triple their volume, minus the time for control tumors to triple their volume. Results: Consistent with theory, increasing the magnitude of the pH gradient by decreasing the extracellular pH increased chlorambucil induced tumor growth delay, and reduced the tumor growth delay induced by the weak base doxorubicin. Conclusions: These results indicate that the pH gradient is an operative determinant of the cytotoxicity of weak electrolyte chemotherapeutics in-vivo. They further suggest that the naturally occurring pH gradient difference between tumor and normal tissue may be exploited for the treatment of cancer by the design of chemotherapeutics with weak acid properties and appropriate pKas. Supported by NCI Grant #RO1 CA92336.

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2005 RRS