A randomized, double-blind, placebo-controlled study of B-cell lymphoma 2 homology 3 mimetic gossypol combined with docetaxel and cisplatin for advanced non-small cell lung cancer with high expression of apurinic/apyrimidinic endonuclease 1

Abstract

Summary Background Overexpression of apurinic/apyrimidinic endonuclease 1 (APE1) is an important cause of poor chemotherapeutic efficacy in advanced non-small cell lung cancer (NSCLC) patients. Gossypol, a new inhibitor of APE1, in combination with docetaxel and cisplatin is believed to improve the efficacy of chemotherapy for advanced NSCLC with high APE1 expression. Methods Sixty-two patients were randomly assigned to two groups. Thirty-one patients in the experimental group received 75 mg/m2 docetaxel and 75 mg/m2 cisplatin on day 1 with gossypol administered at 20 mg once daily on days 1 to 14 every 21 days. The control group received placebo with the same docetaxel and cisplatin regimen. The primary endpoint was progression-free survival (PFS); secondary endpoints included overall survival (OS), response rate, and toxicity. Results There were no significant differences in PFS and OS between the experimental group and the control group. The median PFS (mPFS) in the experimental and control groups was 7.43 and 4.9 months, respectively (HR = 0.54; p = 0.06), and the median OS (mOS) was 18.37 and 14.7 months, respectively (HR = 0.68; p = 0.27). No significant differences in response rate and serious adverse events were found between the groups. Conclusion The experimental group had a better mPFS and mOS than did the control group, though no significant difference was observed. Because the regimen of gossypol combined with docetaxel and cisplatin was well tolerated, future studies with larger sample sizes should be performed.

Targeting DNA Damage Response and Repair to Enhance Therapeutic Index in Cisplatin-Based Cancer Treatment

“…A study consisting of sixty-two advanced NSCLC patients with no previous history of platinum-based chemotherapy showed that patients treated with gossypol along with the assigned docetaxel and cisplatin treatment experienced greater PFS and OS than those in the control group receiving placebo along with the same docetaxel and cisplatin regimen. Though there were no significant differences in PFS, OS, and adverse events between treatment and control groups, the addition of gossypol was well tolerated, and the results encourage larger studies to investigate the drug’s therapeutic potential [ 133 ].…”

Systematic Review of Gossypol/AT-101 in Cancer Clinical Trials

“…In three trials, AT-101 was tested combined with one standard chemotherapeutic (1× topotecan, 2× docetaxel) [97,101,102]. Double standard treatment in combination with AT-101 was investigated in four studies [88,96,99,100]. Notably, one cisplatin and radiation regimen was established [57].…”

“…In addition to small cell lung cancer, there are two further double-blind, placebocontrolled, randomized phase II studies evaluating pharmacological activity of gossypol/AT-101 in non-small cell lung cancer [96,101]. Ready at al.…”

New Horizons for the Roles and Association of APE1/Ref-1 and ABCA1 in Atherosclerosis

“…Animal studies [91] APX2014 [91] Gossypol [106] Inhibitor III 3 [107] Endonuclease inhibitor (Compound #3) [108] (Continued)…”

“… 91 Gossypol in combination with docetaxel and cisplatin improved the efficacy of chemotherapy for advanced non-small-cell lung cancer (NSCLC). 106 Inhibitor III showed substantial antileukemic efficacy, 107 and compound #3 affected mitochondrial activity and suppressed colorectal cancer. 108 RN7-60 and RN10-52 had a greater effect than APX3330 on ovarian cancer cells, and RN8-51 had an effect similar to that of APX3330.…”