Stephen A. Matlin

A preliminary clinical study of gossypol in advanced human cancer.

SummaryA total of 34 patients with advanced cancer were given weekly or daily escalating doses of oral gossypol, a cottonseed-oil constituent showing evidence of antineoplastic activity in pre-clinical studies. No major adverse events occurred and there was no evidence of haematological or biochemical disturbance. As determined by dose escalation in 17 patients, the dose-limiting toxicity was emessis in 16 patients. There was no evidence of tumour regression in any of the 20 patients assessed for response. We conclude that gossypol is safe but unlikely to be clinically useful in patients with advanced cancer.

Male antifertility compounds from Tripterygium wilfordii Hook F.

Extracts of the Chinese medicinal plant, Tripterygium wilfordii, cause reversible infertility in male animals. Sub-fractionation studies have now revealed that the plant extracts contain a number of compounds which are potent antifertility agents in male mammals, including the diterpenes triptolide and tripdiolide and an isomer of the latter. A triptolide, 12,13-chlorohydrin, which is a transformation product formed reversibly by interaction of triptolide with HCl, was also found to be active.

Antiproliferative effect of gossypol and its optical isomers on human reproductive cancer cell lines

The antiproliferative effect of gossypol and its optical isomers on various human cell lines of reproductive and nonreproductive tissue origin was studied. Various reproductive cancer cell lines of ovarian, gestational, and testicular origin were highly sensitive (IC50 values of 0.86-1.98) to gossypol. The antiproliferative action of gossypol was not restricted to reproductive cancers, as non-reproductive cancer cell lines were also equally sensitive (IC50 values of 0.69-3.55). In addition, actively proliferating untransformed cells such as fibroblasts and PHA-activated lymphocytes were also sensitive (IC50 values of 0.87-2.51). (-)-Gossypol was 3.6-12.4 times more potent than (+)-gossypol and 1.48-2.65 times more potent than (+/-)-gossypol. The most sensitive indicator of gossypol action was a decrease in DNA synthesis followed by inhibition of protein synthesis and uptake of rhodamine-123 by mitochondria as tested in an ovarian cancer cell line (OVCA 433) and a fibroblast line (Hs27). These results indicate that gossypol possesses a general nonselective antiproliferative action toward human cells in vitro. Further, the pharmacologic activity of gossypol as an antiproliferative agent is primarily attributable to its (-) isomer, which is also the active isomer as a contraceptive.

Gossypol enantiomer ratios in cotton seeds

Abstract Gossypol enantiomer ratios in cotton seeds were measured by HPLC analysis after conversion to the Schiffs base diastereoisomers using l -phenylalanine methyl ester. An enantiomeric excess of (+)-gossypol was found in each variety of Gossypium arboreum , G. herbaceum and G. hirsutum , whereas (−)-gossypol was in excess in each variety of G. barbadense investigated.

Enantiomeric resolution of chiral sulfoxides on polysaccharide phases by HPLC

The enantiomeric resolution of chiral sulfoxides was investigated on amylose (S)-α-methylbenzyl carbamate phase coated on aminopropylated 7 μm silica with 500A diameter pores. This was shown to be very successful in the separation of alkyl/aryl, aryl/aryl, and non-aromatic sulfoxides. The effect of pore size using naked silica was also investigated, demonstrating that the pore size does not affect the resolution.

Chiral high-performance liquid chromatography with cellulose carbamate-coated phases : influence of support surface chemistry on enantioselectivity

Abstract The influence of support surface chemistry on the enantioselectivity and column performance of cellulose tris(3,5-dimethylphenyl carbamate)-coated chiral HPLC phases was investigated. Stable coated phases were produced using underivatised, aminopropylated and octadecylated silica as the support media. For many racemates, underivasised,silica at a 20% (w/w) loading was found to be the most efficient phase.

MODULATION OF RESISTANCE TO ALKYLATING AGENTS IN CANCER CELL BY GOSSYPOL ENANTIOMERS

Several cell lines resistant to alkylating agents possess increased activity of glutathione-S-transferase (GST) drug detoxifying enzymes. Inhibition of certain enzymes of the glutathione redox system may affect cellular sensitivity to alkylators. We report that the (-.)enantiomer of gossypol is a potent and selective inhibitor of GST alpha and GST pi isozymes, and that in combination with buthionine sulfoximine (BSO), causes the enhanced modulation of alkylator resistance in two drug resistant cell lines with increased GST activity. The use of (-)gossypol alone had no effect on the 2-5-fold resistance of MCF-7 Adr and Walker resistant cells to chlorambucil, melphalan and BCNU. Cellular depletion of glutathione with BSO resulted in a 2-4-fold modulation of cell sensitivity to these alkylators. However, the combination of (-)gossypol with BSO resulted in a markedly greater modulation of alkylator sensitivity than with either inhibitor alone. Therefore, the complementary inhibition of glutathione and GST by BSO and (-)gossypol, respectively, produced a synergistic modulation of alkylator cytotoxicity in these drug resistant cell lines. The favorable clinical pharmacokinetics of (-)gossypol suggest its further evaluation for use in combination with BSO and alkylating agents in clinical trials.

Chiral discrimination by HPLC on aryl carbamate derivatives of chitin coated onto microporous aminopropyl silica

Optical resolution of a range of racemic compounds was investigated using bis(aryl carbamate) derivatives of chitin coated onto microporous organosilane-modified silica. The influence on chiral discrimination of factors such as the carbamate/support weight ratio, the nature of polysaccharide, and the influence of the aryl group substituents was investigated. The bis(3,5-dimethylphenyl carbamate) derivative of a noncommerical chitin gave the best results.

Differential effects of the (+)- and (–)-gossypol enantiomers upon Entamoeba histolytica axenic cultures

Abstract— The in‐vitro anti‐amoebic effects of (±)‐, (+)‐, (–)‐gossypol and emetine were tested against axenic trophozoites from five Entamoeba histolytica strains. The (–)‐isomer was more active than the racemate and the (+)‐isomer. These results indicate that the gossypol anti‐amoebic activity is mainly due to its content of (–)‐gossypol in all strains tested.

Flavonoids from Haplophyllum pedicellatum, H. robustum AND H. glabrinum

Abstract Haplophyllum pedicellatum , H. robustum and H. glabrinum all yielded the known compound gossypetin 8,3′-dimethyl ether 3-rutinoside. In addition the first two species afforded isorhamnetin and its 3-rutinoside. A new glycoside, gossypetin 8,3′-dimethyl ether 3-glucoside was obtained from H. pedicellatum together with the 3-malonylrutinoside, 3-malonylglucoside and 3-galactoside of isorhamnetin plus kaempferol 3-malonylglucoside. H. robustum yielded isorhamnetin 7-glucoside and 3-glucoside and quercetin 3-galactoside, while H. glabrinum was found to contain gossypetin 8-methyl ether 3-malonylrutinoside in addition to kaempferol and isorhamnetin 3-glucoside.