Ribonucleotide Reductase

Ribonucleotide reductase (RR) is the enzyme responsible for the production of 2'-deoxynucleotides from ribonucleotides and consists of two subunits. The R1 subunit binds nucleoside diphosphate substrates and also possesses two allosteric nucleoside triphosphate effector sites that govern both overall activity and substrate specificity to ensure a balanced supply of 2'-deoxynucleotides for DNA synthesis. The R2 subunit contains an iron center that generates a tyrosyl free radical that is necessary for the catalytic reaction (82). In addition, the R2 subunit cooperates with a number of oncogenes and therefore is an attractive target for inhibition in cancer therapy (83).

Lorus has developed 20mer P-ODNs to each of these RR subunits. GTI-2040 selectively inhibited the production of the R2 subunit at 200 nM concentrations, resulting in cytotoxicity to a number of human cell lines in vitro (reviewed by Orr [84]). In xenograft studies of GTI-2040 (0.5-30 mg/kg/d intravenously every other day for up to 44 d), antitumor activity was observed in colon, pancreatic, liver, lung, breast, ovarian, brain, lymphoma, and skin cancers (84,85). In addition, tumor regression was noted when GTI-2040 was administered in combination with other chemotherapeutic agents (84,86).

In a phase I study, GTI-2040 (18.5-222 mg/m2/d) was administered by continuous iv infusion for 3 wk followed by 1 wk of rest between cycles to 27 patients with advanced cancer (84,86). Mild toxicities included anorexia, nausea, hypotension, chills, and fever. One patient experienced dose-limiting fatigue, and DLTs of diarrhea and hepatotoxicity were experienced at the highest dose of 222 mg/m2/d. For phase II studies, 185 mg/m2/d (5 mg/kg/d) was recommended. At this level, plasma concentrations of GTI-2040 of approx 1 ^g/ mL were deemed sufficient to achieve target suppression in clinical studies.

Currently, GTI-2040 is in phase II clinical trials in combination with capecitabine for the treatment of renal cell carcinoma. Interim data have shown disease stabilization and tumor responses in some of the 21 evaluable patients.

The sister compound to GTI-2040, GTI-2501, targets the R1 subunit of RR and has displayed target specificity in vitro and in vivo. In human tumor models, GTI-2501 exhibited marked antitumor activity against colon, pancreatic, lung, breast, ovarian, skin, prostate, brain, and renal cancers (87,88). In addition, GTI-2501 prevented metastatic tumor spread and was effective in combination with other chemotherapeutic agents, producing results ranging from pronounced tumor growth delay to complete tumor regressions (88). GTI-2501 has completed phase I studies in patients with advanced cancer and is currently in phase II clinical trials against hormone-refractory prostate cancer.

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