This subproject is one of many research subprojects utilizing theresources provided by a Center grant funded by NIH/NCRR. The subproject andinvestigator (PI) may have received primary funding from another NIH source,and thus could be represented in other CRISP entries. The institution listed isfor the Center, which is not necessarily the institution for the investigator.Two major disadvantages of cisplatin therapy of cancer are the development of drug resistance in the tumor, nephrotoxicity and neurotoxicity. The prodrug amifostine (WR-2721, Ethyol), S-2 [3-aminopropylamino] ethylphosphorothioic acid has been used to protect normal tissues against adverse effects of cancer therapy with cisplatin. However, whether amifostine compromises cancer treatment efficacy by protecting the tumor is not clearly resolved. In clinical studies of amifostine administration along with cisplatin have not been sufficiently long to detect any treatment failures (i.e., tumor recurrence) that can be attributed to the use of amifostine in combination with cisplatin. This is intriguing because the prodrug amifostine is dephosphorylated by alkaline phosphatases (present in normal tissues and vasculature and certain tumors including lung cancer) to the active amino thiol form of the drug, WR-1065. Thiols can chemically inactivate cisplatin and other drugs. The lack of amifostine mediated inactivation of cisplatin and other drugs during cancer treatment may be due to inadequate distribution of amifostine and its metabolite (relative to cisplatin) in poorly vascularized tumors, which may be deficient in alkaline phosphatase. This bears further scrutiny in view of the numerous reports associating alkaline phosphatase with a variety of tumors. Tumors differ with respect to thiol content, alkaline phosphatase activity, and vascular density. Therefore tumors will differ in their ability to activate the prodrug amifostine. Several tumor cell lines were surveyed and found to differ considerably with respect to their alkaline phosphatase activity and consequently their ability to activate the prodrug amifostine to its active thiol form. Inhibitors of alkaline phosphatase altered the kinetics of dephosphorylation of amifostine. This underscores the importance of identifying tumors with high alakaline phosphatase levels, since amifostine will be protect against cisplatin. Noninvasive techniques for monitoring dephosphorylation of amifostine in tumors will permit individualization of treatment strategies. We have found that a nitric oxide (NO) donor such as nitroaspirin is cytotoxic to cisplatinum resistant cancer cells which contain high levels of thiols. Such NO donors may be useful in cancer therapy.
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