OVERCOMING ALKYLTRANSFERASE-RELATED DRUG RESISTANCE

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Tumor cell resistance mechanisms reduce the effectiveness of chemotherapeutic drugs. The activity of DNA repair enzymes are a major cause of resistance, especially to the nitrosoureas (such as BCNU) and related alkylating agents. BCNU forms adducts at the O6 position of guanine, and the adducts subsequently react with cytosine residues on the opposite strand causing crosslinks that are cytotoxic to cells. These adducts are repaired by the DNA repair enzyme 06-alkylguanine DNA alkyltransferase (AGT), in a reaction that irreversibly inactivates the enzyme. Restoration of the enzyme requires the synthesis of new molecules. In preclinical studies, intracellular activity of the enzyme correlates well with the cytotoxicity of BCNU, and depletion of the enzyme enhances effectiveness of the drug. A specific inhibitor of AGT, O6-benzylguanine (BG), has been shown to deplete AGT activity in in- vitro and in-vivo preclinical studies, and to date has been shown to be relatively non-toxic. This grant proposes a series of Phase I and Phase II clinical trials designed to establish whether AGT depletion in tumor tissue with BG is feasible and safe, and whether the combination of BG and BCNU can enhance efficacy in tumors known to have high levels of AGT, but whose responses to BCNU are poor. A key feature of these studies is the incorporation of novel techniques with which to measure AGT activity directly in tumor tissue, and to correlate these levels with the kinetics of BG.The initial Phase I trial is designed specifically to determine the biochemical modulatory dose (BMD) of BG required to deplete tumor tissue AGT, to assess the pharmacokinetics of BG, to evaluate peripheral blood mononuclear cell levels of AGT as a possible surrogate of tumor tissue AGT, and to assess the maximum tolerated dose of BCNU in combination with the BMD of BG. This trial will be followed by two Phase II trials in metastatic malignant melanoma patients, and in patients with multiple myeloma, in which the clinical efficacy of the BG plus BCNU combination will be tested. A further Phase I trial will assess the dose escalation of BCNU using stem cell rescue as a means of avoiding myelotoxicity of the BG and BCNU combination which is predicted from preclinical studies. This approach of monitoring pharmacodynamic events at a cellular level holds promise as a prototype for the future development of cytotoxic agents.