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Gossypol

Scientific Name(s): Gossypium spp.
Common Name(s): ApoG2, AT-101, Gossypol

Clinical Overview

Use

According to Chinese studies, gossypol is effective as a nonhormonal male contraceptive; however, it has been documented to have irreversible effects on male fertility and is not recommended for this use. Gossypol is being studied for clinical applications in cancer therapy with equivocal results.

Dosing

Antifertility: There are no dosing recommendations for gossypol due to its potential irreversible effects on male fertility. Cancer: Maximum tolerated dosage appears to be 40 mg/day of gossypol (as AT-101).

Contraindications

None well documented.

Pregnancy/Lactation

Avoid use. Documented abortifacient effects.

Interactions

None well documented.

Adverse Reactions

Nausea, emesis, anorexia, diarrhea, altered taste sensation, small intestine obstruction, and fatigue have been reported in clinical trials. The irreversible effects of gossypol on male fertility have been well documented, as has the incidence of hypokalemia. Dose-limiting elevations in liver enzymes have been noted at total doses of 60 mg/day for AT-101, and an increased incidence of hematological toxicities has been observed when AT-101 is combined with cancer chemotherapy, depending on the regimen.

Toxicology

No data.

Botany

Gossypol is derived from members of the family Malvaceae. The stem, seed, and root of the cotton plant Gossypium hirsutum represent the most common sources of gossypol. Gossypium species are shrubs that grow to a height of 3 m, have broad lobed leaves, and contain seeds in a capsule or "boll" of fibers. These fibers are harvested and woven in the textile industry. The seeds of Gossypium species vary widely in gossypol content, with levels ranging from 0.13% to 6.6%.USDA 2010, Wang 2009

History

Gossypol was first identified as an antifertility agent as a result of epidemiologic studies conducted in China during the 1950s. Investigators had noted extremely low birth rates in a particular geographic region and found the men in the region had very low sperm counts and many women had amenorrhea. Eventually the phenomenon was attributed to the use of crude cottonseed oil for cooking and the consumption of cotton cake left over after extraction of the oil and fiber from the cotton plant. Further investigation revealed that the antifertility component was gossypol; crystalline extracts were then supplied to Chinese doctors for widespread use in the 1970s as the principle contraceptive method in China. However, irreversible effects on fertility and cases of hypokalemia led to a reduced scientific interest in gossypol.Coutinho 2002

Chemistry

Gossypol is a polyphenolic compound that can be made synthetically or produced inexpensively on a very large scale by the extraction of cottonseed. Different versions of the compound have been developed to improve efficacy and reduce toxicity of the original chemical. Apogossypolone (ApoG2) and R-(-)-gossypol (AT-101) have been used in clinical trials.Azmi 2009, Cheson 2009, Wang 2009, Zhan 2009

Uses and Pharmacology

Antifertility/Contraceptive

Gossypol is a nonsteroidal compound that inhibits sperm production and motility in a variety of male animals and in humans, but it does not affect sex hormone levels or libido. Gossypol exerts its contraceptive action by inhibiting enzyme systems that play a crucial role in energy metabolism in sperm and spermatogenic cells.Coutinho 2002, Wang 2009

Animal data

Gossypol has been used as an active antifertility agent in a variety of male animals, including mice, rats, hamsters, monkeys, rabbits, and bulls.Wang 2009

Clinical data

In large-scale clinical trials conducted by Chinese investigators, gossypol was orally active and effective as a contraceptive in men. Clinical testing of gossypol began in the early 1970s in China and the drug has since been studied extensively in thousands of men. Reviews of the clinical trials of gossypol have been published.Lopez 2005, Wu 1989

Clinical trials focus on establishing lower dosages in an attempt to reduce the potential for hypokalemia and irreversible effects on male fertility. Trials have used 10, 12.5, and 15 mg daily for 2 to 3 months to achieve azoospermia, with maintenance dosages of 35 to 43.75 mg weekly and 7.5 to 10 mg daily tested for up to 2 years.Coutinho 2002, Gu 2000

Sperm counts usually return to normal in about 50% of men within 3 months after termination of therapy, and men treated with gossypol have fathered healthy children. However, long-term follow-up studies indicate that inhibition of spermatogenesis may continue in up to 50% of men after 2 years following discontinuation. Spermatogenesis does not return to normal in some men. Concerns regarding the lack of predictable, reversible effects have delayed the further clinical development of gossypol in Western countries.Coutinho 2002 The use of gossypol as a nonhormonal alternative to high-dose estrogen in transsexual patients has been suggested.Yurekli 2009

Antiviral, antibacterial, antiprotozoal activity

Gossypol and its derivatives have demonstrated antiviral, antibacterial, and antiprotozoal activity.Wang 2009

Cancer

Gossypol inhibits the growth of various cancer cell lines in vitro, including breast, colon, prostate, and leukemia. Inhibition of cytoplasmic and mitochondrial enzymes (including key enzymes for DNA replication and repair), uncoupling of oxidative phosphorylation, and depletion of cellular ATP are proposed mechanisms of action.Azmi 2009, Banerjee 2010, Cheson 2009, Liu 2009, Reddish 2010, Rodríguez-Enríquez 2009, Van Poznak 2001, Wang 2009, Xu 2009, Yan 2010, Zhang 2010

Animal data

Gossypol inhibited tumor growth in mice within 7 days in 1 experiment and reduced tumor size by 65% in another at dosages of 30 mg/kg/day.Rodríguez-Enríquez 2009, Yan 2010, Zhang 2010

In a mouse model of ovarian cancer, 50 mg/kg of gossypol combined with carboplatin demonstrated greater decreases in tumor size (94%) compared to either treatment alone (64% and 51%, respectively).Qu 2017

Clinical data

Phase 1 and 2 clinical trials are being conducted using gossypol enantiomer AT-101 in non-Hodgkin lymphomas and breast and prostate cancer.Cheson 2009, Liu 2009, Van Poznak 2001 Limited efficacy has been demonstrated, with effects on surrogate outcomes such as Rb protein and cyclin D1 expression in a breast cancer study and decreased prostate-specific antigen in a prostate cancer study. Maximum tolerated dosages appeared to be 40 mg/day.Van Poznak 2001 Phase 2 trials in men with metastatic prostate cancer have indicated a slight worsening of response and/or increased adverse events with the addition of AT-101 to standard therapy.Sonpavde 2012, Stein 2016 In an effort to delay progression to castrate-resistant disease, AT-101 was added to androgen deprivation therapy in men with newly diagnosed castration-sensitive metastatic prostate cancer in a single-arm phase 2 study (n=33). After 7.5 months, the percentage of men achieving an undetectable prostate-specific antigen level was 31%, which was below the 48% benchmark.Stein 2016 In another phase 2 trial, 221 men with castrate-resistant metastatic prostate cancer were randomized in a double-blind manner to receive docetaxel and prednisolone plus AT-101 or placebo for up to 1 year. No difference was observed in overall or progression-free survival rates between groups. The incidence of adverse events was higher in the AT-101 group, which led to a higher proportion of patients requiring discontinuation (27.3% vs 16.4%) and dose reductions (21.8% vs 13.6%) compared with placebo. Adverse effects occurring at a higher incidence in the treatment group compared with placebo included pulmonary embolism (6% vs 2%), cardiac events (5% vs 2%), lymphopenia (23% vs 16%), neutropenia (47% vs 40%), ileus (2% vs 0%), and peripheral neuropathy (24% vs 13%).Sonpavde 2012 Similar phase 1/2 study results have been reported with AT-101 combination therapy in patients with extensive-stage, refractory, or recurrent small cell lung cancer, with 3 trials stopped early due to lack of efficacy at the interim analysis.Baggstrom 2011, Heist 2010, Ready 2011, Schleman 2014

Tolerability of AT-101 as an adjunct to standard cisplatin-based chemoradiotherapy is being assessed in adult patients with inoperable head and neck squamous cell carcinoma in an ongoing phase 1/2 trial. Secondarily, assessment of pharmacokinetic parameters revealed a dose-dependent increase in plasma levels, which peaked between 1.5 and 2.5 hours after administration at concentrations of 300 and 700 ng/mL for 10 (n=13) and 20 mg doses (n=1), respectively. Peak levels corresponded to 0.6 to 1.35 mcM of AT-101. No results were reported regarding tolerability. Results from concomitant in vitro studies supported the role of AT-101 as a potent enhancer of radiation-induced apoptosis.Zerp 2015

A 5-year experiment in 1 patient with chronic lymphocytic leukemia suggested that daily consumption of milk from cows fed supplemental cottonseed and/or cottonseed oil results in a greater reduction in lymphocyte count (54% reduction) than milk from cows not given the supplement (28.5% reduction). Additionally, supplementing the patient's diet with refined edible cottonseed oil containing 455 mg/kg of free gossypol and no bovine milk for 34 days led to a 36% reduction in lymphocyte count. Also in this patient, milk with higher vitamin D content had previously been shown to reduce lymphocyte counts more than bovine milk with lower levels of vitamin D.Politzer 2008

Cholesterol

Animal data

An effect on plasma cholesterol has been demonstrated in animals.Wang 2009

Female contraception

Animal data

Although gossypol is generally considered to be a male antifertility agent, it is also effective when given to female animals.Cameron 1982

Clinical data

Gossypol has been evaluated as a topical spermicide in women; however, this line of study has not been pursued.Ratsula 1983

Dosing

Antifertility

There are no dosing recommendations for gossypol due to its potential irreversible effects on male fertility. Clinical trials have used gossypol 10, 12.5, and 15 mg daily for 2 to 3 months to achieve azoospermia, with maintenance dosages of 35 to 43.75 mg weekly and 7.5 to 10 mg daily for up to 2 years.Coutinho 2002, Gu 2000

Cancer

Maximum tolerated dosage appears to be 40 mg/day of gossypol (as AT-101).Van Poznak 2001

Pregnancy / Lactation

Avoid use. Documented abortifacient effects.

Intramuscular injection of gossypol in female rats inhibited implantation and maintenance of normal pregnancy, most likely due to effects on luteinizing hormone levels.Lin 1985

Interactions

None well documented.

Adverse Reactions

The sometimes irreversible effects of gossypol on male fertility have been well documented, as has the incidence of hypokalemia.Wang 2009

Clinical trials evaluating AT-101 in cancer have reported adverse effects such as nausea, emesis, anorexia, diarrhea, altered taste sensation, small intestine obstruction, and fatigue.Liu 2009, Van Poznak 2001 Dose-limiting elevations in liver enzymes have been noted at total doses of 60 mg/day for AT-101.Heist 2010 Although clinically important hematologic toxicities have not been observed when AT-101 is used as a single agent in cancer studies, additional marrow suppression appears to occur with AT-101 when combined with chemotherapy agents and varies depending on the chemotherapy regimen used. In one phase 1 trial, the increased incidence of hematological toxicity with 40 mg of AT-101 was mitigated with the addition of filgrastim to the cisplatin-etoposide treatment regimen.Schleman 2014

In a 2016 American Heart Association scientific statement regarding drugs that may cause or exacerbate heart failure, gossypol was recognized as a product with possibly harmful cardiovascular effects (eg, increased effects of diuretics) that could potentially be harmful in patients with heart failure. The statement noted that nutraceuticals are not recommended for the management of heart failure symptoms or for the secondary prevention of cardiovascular events and that nutritional supplements are not recommended for the treatment of heart failure.Page 2016

Toxicology

Dose-dependent acute, subchronic, and chronic toxicity has been demonstrated in animals.

Circulatory failure and pulmonary edema are consequential to the cardiotoxicity of gossypol, thought to be due to the prevention of oxygen release from oxyhemoglobin and interference in enzymatic processes. Hepatotoxicity has been observed in some animal studies.de Peyster 1979, Final Report 2001, Kovacic 2003, Wang 2009

Cottonseed oil was nontoxic in short-term oral administration studies in rats because the gossypol content was generally low, with extraction processes possibly influencing the amount of gossypol obtained. However, an increase in the incidence of mammary tumors was observed in some studies. Apogossypol is suggested to have a lower toxicity profile.de Peyster 1979, Wang 2009

The compound was not mutagenic when tested in the Ames Salmonella microsome test, but questions remain about its genotoxic characteristics.de Peyster 1979 Teratogenicity studies found no adverse effect on fetuses or pregnancy in rats administered 40 mg/kg body weight.Coutinho 2002

References

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