Abstract
Clinical ribonucleotide reductase (RNR) inhibitors have reinvigorated enthusiasm for radiochemotherapy treatment of patients with regionally advanced stage cervical cancers. About two-thirds of patients outlive their cervical cancer (1), even though up to half of their tumors retain residual microscopic disease (2). The National Cancer Institute Cancer Therapy Evaluation Program conducted two prospective trials of triapine–cisplatin–radiation to improve upon this finding by precisely targeting cervical cancer’s overactive RNR. Triapine’s potent inactivation of RNR arrests cells at the G1/S cell cycle restriction checkpoint and enhances cisplatin–radiation cytotoxicity. In this article, we provide perspective on challenges encountered in and future potential of clinical development of a triapine–cisplatin–radiation combination for patients with regionally advanced cervical cancer. New trial results and review presented here suggest that a triapine–cisplatin–radiation combination may offer molecular cell cycle target control to maximize damage in cancers and to minimize injury to normal cells. A randomized trial now accrues patients with regionally advanced stage cervical cancer to evaluate triapine’s contribution to clinical benefit after cisplatin–radiation (clinicaltrials.gov, NCT02466971).
Highlights
Cervical cancer forecasts as the fourth most common any-type cancer in women worldwide in 2018 [3]
About 36% of new cases in American women are staged as regionally advanced at first diagnosis [4]. This means that their disease is confined in the cervix or nearby organs or lymph nodes (International Federation of Gynecology and Obstetrics stage IB2 to IVA). Patients with this stage of disease undergo once weekly cisplatin chemotherapy (40 mg m−2) and daily radiation (180 cGy per Monday to Friday) repeated for 5 weeks followed by intracavitary brachytherapy [1, 5]
It was shown that triapine strongly arrested cells at a G1/S-phase cell cycle restriction checkpoint for up to 18 h, left radiation-induced DNA damage unrepaired for at least 6 h, and profoundly sensitized cancers to radiation–cisplatin cytotoxicity [20,21,22, 30]
Summary
Clinical ribonucleotide reductase (RNR) inhibitors have reinvigorated enthusiasm for radiochemotherapy treatment of patients with regionally advanced stage cervical cancers. The National Cancer Institute Cancer Therapy Evaluation Program conducted two prospective trials of triapine– cisplatin–radiation to improve upon this finding by precisely targeting cervical cancer’s overactive RNR. We provide perspective on challenges encountered in and future potential of clinical development of a triapine–cisplatin–radiation combination for patients with regionally advanced cervical cancer. New trial results and review presented here suggest that a triapine–cisplatin–radiation combination may offer molecular cell cycle target control to maximize damage in cancers and to minimize injury to normal cells. A randomized trial accrues patients with regionally advanced stage cervical cancer to evaluate triapine’s contribution to clinical benefit after cisplatin–radiation (clinicaltrials.gov, NCT02466971)
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