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Abstract

Gossypol, a polyphenolic compound which depletes cellular energy by inhibition of several intracellular dehydrogenases, has been shown to have antiproliferative activity against human glial tumor cell lines in vitro and in nude mouse xenografts. Human trials of gossypol as a male contraceptive have demonstrated safety of long-term administration. We studied the activity of Gossypol 10 mg PO bid in 27 patients with pathologically confirmed glial tumors which had recurred after radiation therapy. Fifteen patients had glioblastoma, 11 patients anaplastic astrocytoma, 1 patient relapsed low grade glioma. Response was assessed every 8 weeks using CT/MRI scan and clinical criteria including decadron requirement. Treatment was continued until disease progression. Two patients had partial response (PR); 4 had stable disease for 8 weeks or more. One patient maintained a PR with improved KPS for 78 weeks. The other had a PR lasting 8 weeks. Toxicity was mild: 2 heavily pretreated patients had mild thrombocytopenia, 5 patients developed hypokalemia, 3 patients developed grade 2 hepatic toxicity and peripheral edema. Gossypol levels measured by HPLC did not correlate with response or toxicity in this study. We conclude that gossypol is well tolerated and has a low, but measurable, response rate in a heavily pretreated, poor-prognosis group of patients with recurrent glioma. The presumed novel mechanism of action, lack of significant myelosuppression, and activity in patients with advance glioma support further study of gossypol as an antineoplastic agent.

Anti-tumor Therapeutic Molecules that Target the Programmed Cell Death Machinery

“…Similar to this study, tissue culture studies in other cancer cell lines have shown that the (-) enantiomer of Gossypol has a more potent toxic effect than the (+) enantiomer [50,51]. While it has been reported that racemic gossypol is active against many cancer cell lines both in vitro and in vivo, it also generated toxic side effects in phase-1 clinical trials possibly due to the fact that it contains two aldehydes [52,53]. Therefore, attempts to produce less toxic derivatives of Gossypol that still retain the Bcl-2 inhibitory function have resulted in the synthesis of Apogossypol (2), which lacks the two aldehyde groups [54].…”

Programmed Cell Death Pathways and Current Antitumor Targets

“…For example, in a previous clinical study carried out in 23 patients with advanced refractory solid tumors, none of the patients showed evidence of tumor regression during treatment (73). A phase II trial of gossypol (10 mg orally twice daily) performed in 27 patients with pathologically confirmed recurrent glial tumors showed low treatment response and their plasma levels did not correlate well with response or toxicity (74). In another phase I/II study of 20 women with metastatic breast cancer refractory to doxorubicin and paclitaxel, the drug produced no therapeutic responses (75).…”

Mechanism of Drug and Toxic Actions of Gossypol: Focus on Reactive Oxygen Species and Electron Transfer

“…Studies have continued into more recent times with varying results involving different types of cancer. A selection of references is presented for some of the more promising clinical and preclinical trials [41][42][43], in addition to reports on preclinical studies on mice and rats [44][45][46].…”