Triapine Radiochemotherapy in Advanced Stage Cervical Cancer

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 (, NCT02466971).

Randomized Phase II Trial of Triapine-Cisplatin-Radiotherapy for Locally Advanced Stage Uterine Cervix or Vaginal Cancers

“…For this reason, metabolic complete response was regarded by NCI and by ACRIN as clinically meaningful in assessing the antitumor activity of triapine. The metabolic complete response rate by SUV uptake ratio in the triapine group of 92% is consistent with a long-term 95% metabolic complete response rate seen in previous triapine-cisplatin-radiotherapy clinical trials (30). The generalizability and transferability of the metabolic complete response findings in this study are limited; the on-going phase III trial of triapine-cisplatin-radiotherapy is adequately powered to evaluate better the metabolic complete response in uterine cervix or vaginal cancers (NCT02466971).…”

Palladium(ii) complexes with thiosemicarbazones derived from pyrene as topoisomerase IB inhibitors

“…5 Dp44mT is structurally similar to triapine (Chart 1), a compound which has undergone Phase 1 and 2 clinical trials. 6,7 Both topoisomerase I (Top I) and topoisomerase II (Top II) have been established as effective molecular targets for many antitumor drugs. Several transition metal complexes have been shown to react with topoisomerase IB and act as poisons and/or catalytic inhibitors, since tumor cells present high levels of Top enzymes.…”

Combining novel agents with radiotherapy for gynecologic malignancies: beyond the era of cisplatin

“…Triapine (NSC #663249) is an inhibitor of the M2 subunit of ribonucleotide reductase, the rate-limiting enzyme required for DNA-building deoxyribonucleotides 70. Through this molecular inhibition, triapine can prolong DNA repair time and arrest cancer cells at the G 1 /S cell cycle restriction checkpoint, thereby increasing their vulnerability to radiation therapy-induced death 71. The activity and tolerability of triapine has been evaluated in colon72 and pancreatic cancer,73 and triapine has shown promise in cervical cancer, which is associated with overactive ribonucleotide reductase 71.…”

“…Through this molecular inhibition, triapine can prolong DNA repair time and arrest cancer cells at the G 1 /S cell cycle restriction checkpoint, thereby increasing their vulnerability to radiation therapy-induced death 71. The activity and tolerability of triapine has been evaluated in colon72 and pancreatic cancer,73 and triapine has shown promise in cervical cancer, which is associated with overactive ribonucleotide reductase 71. The National Cancer Institute undertook two single-arm prospective trials, phase I (7336) and phase II (8327), to evaluate the combination of triapine and cisplatin with radiation therapy for advanced cervical cancer; this combination resulted in auspicious results including a 3 year pelvic loco-regional relapse rate of 4%, disease-free survival of 80%, and overall survival of 82%, with only 25% of patients experiencing an acute attributable grade 3 or 4 toxicity (mostly transient cytopenias) and 8% experiencing late toxicity (mostly vaginitis) 70.…”