© 2000 by Oxford University Press
Journal of the National Cancer Institute, Vol. 92, No. 11, 855,
June 7, 2000
© 2000 Oxford University Press
IN THIS ISSUE |
P-glycoprotein-mediated multidrug resistance complicates cancer chemotherapy and treatment of patients infected with human immunodeficiency virus. Loo and Clarke (p. 898) examined the effects of disulfiram (AntabuseTM), a drug used to treat alcoholism, on cellular sensitivity to drugs and the maturation of P-glycoprotein. In embryonic kidney cells transfected with the P-glycoprotein gene, 100 nM disulfiram increased sensitivity to two cytotoxic agents. In cells with a modified form of the gene, 50 nM disulfiram blocked maturation of the protein. The authors conclude that disulfiram may improve the efficacy of drug regimens for acquired immunodeficiency syndrome and cancer.
"Our results suggest that drug regimens that include disulfiram should be clinically tested for their potential to improve the efficacy of cancer and [AIDS] chemotherapies."
—Loo and Clarke
Buserelin, Tamoxifen, and Premenopausal Breast Cancer
Common endocrine treatments for premenopausal women with breast cancer are surgical or medical castration and antiestrogen treatment with tamoxifen. However, tamoxifen therapy induces high levels of plasma estradiol in these women with unknown long-term effects. Klijn et al. (p. 903) report results of a randomized clinical trial in premenopausal women that compared a combined treatment of tamoxifen and buserelin (a luteinizing hormone-releasing hormone agonist that suppresses the secretion of estrogen by the ovaries) with treatment with either drug alone. They found that the combined treatment was superior to treatment with either drug alone by objective response rate, median progression-free survival, and overall survival. They report that, during treatment with tamoxifen alone, plasma estradiol levels increased threefold to fourfold over levels before treatment and remained elevated throughout treatment. However, during combined treatment or treatment with buserelin alone, plasma estradiol levels were suppressed equally.
In an editorial, Davidson (p. 859) discusses what the results of Klijn et al. and of others might teach us about approaches to adjuvant therapy and chemoprevention of breast cancer. She suggests that a combined approach involving combined ovarian ablation and selective estrogen receptor modulators (SERMs) may be worthy of study in certain premenopausal women who have a high risk of developing breast cancer.
PTEN Expression as a Diagnostic Marker
Uncertainties in precancer diagnosis have made it difficult to determine if altered function of the PTEN gene precedes the appearance of endometrial intraepithelial neoplasia. Mutter et al. (p. 924) analyzed endometrial cancer and precancer tissue samples for PTEN gene mutations and PTEN protein expression. PTEN mutations were found in 83% of cancer tissue samples and in 55% of precancerous lesions. There were a statistically significantly greater number of PTEN mutations in the cancer tissue samples, and 97% of these samples showed immunohistochemical evidence of reduced protein expression. The authors conclude that loss of PTEN function is an early event in endometrial tumorigenesis and that it may offer an informative biomarker for premalignant disease.
In an editorial, Ali (p. 861) points out that the PTEN gene is well suited to play multiple roles in many cell types and that the PTEN protein probably regulates overlapping signaling pathways that affect many vital cellular processes. She concludes that understanding the PTEN gene’s activities at the molecular level should help identify molecular targets for the prevention and treatment of cancer.
"Use of PTEN immunostaining . . . may be informative in identifying premalignant lesions."
—Mutter et al.
Tumor Cell Gangliosides and Tumor Formation
Tumor cells often have a high concentration of gangliosides (immunosuppressive cell surface molecules that inhibit the antitumor immune response). To determine the impact of cellular gangliosides on tumor formation, Deng et al. (p. 912) pharmacologically depleted the gangliosides from a ganglioside-rich subline of B16 melanoma cells, MEB4, and determined the ability of these cells to form tumors in mice. They found that although depleting the MEB4 cells’ ganglioside content did not kill these cells or inhibit their ability to proliferate in vitro, it reduced their ability both to form tumors and to metastasize, compared with untreated MEB4 cells. The authors suggest that pharmacologic depletion of gangliosides should be explored further as therapy for cancer.
Identification of Individuals With K-ras Mutations
Kopreski et al. (p. 918) investigated the feasibility of detecting cancer-associated somatic mutations of the K-ras gene in plasma DNA. They collected plasma samples from 240 patients undergoing colonoscopy, risk factor information from 232 patients, and colorectal biopsy information from 135 patients. K-ras mutations were seen in 64 (28%) of 232 plasma samples and showed a statistically significant association with colorectal cancer risk factors. Of the 35 patients with mutations in the tissue, 29 (83%) also showed mutations in plasma. In contrast, among 100 patients whose tissue K-ras was wild-type, 93 showed no mutations in plasma DNA. Overall, 39% of patients with mutations in plasma DNA also had colorectal neoplasms with mutations, compared with positive tissue findings in only 3% of those without K-ras mutations in plasma DNA. The authors conclude that plasma DNA assays for K-ras mutations may provide a feasible method to screen populations for somatic mutations frequently found in neoplasms.
"Plasma-based assays . . . offer a minimally invasive method for somatic mutation screening."
—Kopreski et al.
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