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.
Unable to display preview. Download preview PDF.
- 4.Timperley W: Lactate dehydrogenase isozymes in tumors of the nervous system. Acta Neuropathol (Berl) 19: 20–24, 1974Google Scholar
- 5.Gerhardt W, Clausen J, Christensen E, Riishede J: Lactate dehydrogenase isoenzymes in the diagnosis of human benign and malignant brain tumors. J Nat Canc Inst 38(3): 343–57, 1967Google Scholar
- 7.Egami H, Takeshita I, Fukui M, Kitamura K: Supernumerary lactate dehydrogenase isozymes in human gliomas. J Neurolog Sci 61(1): 1–12, 1983Google Scholar
- 11.Tso WW, Lee CS: Lactate dehydrogenase-X: an isozyme particularly sensitive to gossypol inhibition. Internat J Androl 5(2): 205–9, 1982Google Scholar
- 13.Ligueros M, Jeoung D, Tang B, Hochhauser D, Reidenberg M, Sonenberg M: Gossypol inhibition of mitosis, cyclin D1 and Rb protein in human mammary cancer cells and cyclin-D1 transfected human fibrosarcoma cells. Brit J Canc 76(1): 21–8, 1997Google Scholar
- 15.Seghal A: Molecular changes during the genesis of brain tumors. Sem Surg Onc 14(1): 3–12, 1998Google Scholar
- 17.Coyle T, Levante S, Shetler M, Winfield J: In vitro and in vivo cytotoxicity of gossypol against central nervous system tumor cell lines. J Neuro-oncol 19(1): 25–35, 1994Google Scholar
- 18.Wu DF, Yu YW, Tang ZM, Wang MZ: Pharmacokinetics of (C=+)-, (C)-, and (+)-gossypol in humans and dogs. Clin Pharm Therapeut 39(6): 613–8, 1986Google Scholar
- 19.Flack MR, Pyle RG, Mullen NM, Lorenzo B, Wu YW, Knazek RA, Nisula BC, Reidenberg MM: Oral gossypol in the treatment of metastatic adrenal cancer. J Clin Endocrinol Metabol 76(4): 1019–24, 1993Google Scholar
- 20.Han ML, Wang YF, Tang MY, Ge QS, Zhou LF, Zhu PD, Sun YT: Gossypol in the treatment of endometriosis and uterine myoma. Contribut Gyn Obstet 16: 268–70, 1987Google Scholar
- 25.Strom-Hansen T, Cornett C, Jaroszewski JW: Interaction of gossypol with amino acids and peptides as a model of enzyme inhibition. Internat J Pept Prot Res 34(4): 306–10, 1989Google Scholar
- 29.Zhou LF, Lei HP: (Effect of gossypol acetic acid on the uterus and ovary) (Chinese). Yao Hsueh Hsueh Pao – Act Pharm Sin 19(3): 220–3, 1984Google Scholar
- 30.Brada M, Sharpe G: Chemotherapy of high-grade gliomas: beginning of a new era or the end of the old? Eur J Canc 32A(13): 2193–4, 1996Google Scholar