© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 16, 1187,
August 15, 2001
© 2001 Oxford University Press
IN THIS ISSUE |
BRCA1 and BRCA2 are the major genes involved in inherited susceptibility to breast cancer. Most studies published to date are based on selected groups of patients and their families recruited from high-risk referral clinics, which makes it difficult to evaluate the role that mutations in these genes play in the general population. Loman et al. (p. 1215) studied BRCA1 and BRCA2 mutations in women diagnosed with breast cancer before the age of 41 years in southern Sweden from 1990 through 1995, along with the history of breast and ovarian cancers among their family members, using two different inclusion schemes to evaluate family history. They found that about half of the women studied had some family history of breast cancer. They estimate that BRCA1 or BRCA2 mutations accounted for 9% of early-onset breast cancer.
In an editorial, Berry (p. 1188) presents possible reasons for the low prevalence estimates observed by Loman et al. He also discusses the relevance of population-based studies, such as this one, to clinical practice involving counseling women at risk for familial breast cancer.
4-HPR and hTERT Expression in Bronchial Epithelia
The human telomerase reverse transcriptase catalytic subunit (hTERT) is the rate-limiting component of the ribonucleoprotein telomerase, an enzyme whose activity is detectable in most human tumors but not in the corresponding benign tissues. Soria et al. (p. 1257) evaluated the frequency of hTERT messenger RNA (mRNA) expression in bronchial biopsy specimens obtained from cigarette smokers enrolled in a randomized, placebo-controlled trial of N-(4-hydroxyphenyl)retinamide (4-HPR) in chemoprevention of squamous metaplasia. The authors found that the percentage of biopsy specimens that expressed detectable hTERT mRNA after 6 months of treatment with 4-HPR decreased from 62% to 46%, whereas the percentage of biopsy specimens that expressed detectable hTERT mRNA after 6 months of treatment with placebo increased slightly from 65% to 68%. The authors conclude that hTERT expression is a very early event in cigarette smoking-induced lung carcinogenesis and that 4-HPR reduces hTERT expression in the bronchial epithelium of smokers.
In an accompanying editorial, Pastorino (p. 1190) describes the basis for general skepticism toward lung cancer chemoprevention and suggests that future intervention trials should concurrently evaluate expression of a panel of molecular markers, including hTERT.
Effects of Carnosic Acid on Monocytic Differentiation
The agents 1,25-dihydroxyvitamin D3, all-trans-retinoic acid (ATRA), and 12-O-tetradecanoylphorbol-13-acetate (TPA) induce monocytic differentiation in myeloid cells. Carnosic acid, a plant-derived polyphenol often used as a food preservative, potentiates the effects of these agents. Danilenko et al. (p. 1224) examined the mechanisms associated with this potentiation in the myeloid leukemia cell line HL60-G. Monocytic differentiation induced by each of the agents was enhanced by carnosic acid, as shown by increased expression of specific markers, decreased cellular proliferation, and blocked cell cycle transition from G1 to S phase. Carnosic acid alone increased the expression of vitamin D receptor and retinoic acid (or retinoid-X) receptor-
, but expression was greatly enhanced in the presence of 1,25-dihydroxyvitamin D3 or ATRA (or TPA). The authors conclude that the identification of downstream regulators of monocytic differentiation should provide new approaches to combined chemoprevention or differentiation therapy for myeloid leukemia.
Orally Active Taxanes and P-Glycoprotein Modulation
Some tumor cells acquire resistance to the chemotherapeutic taxane paclitaxel through overexpression of P-glycoprotein (Pgp), an efflux pump that removes the drug from cells. The paclitaxel analogue IDN-5109 is reported to overcome Pgp-mediated drug resistance. Vredenburg et al. (p. 1234) tested whether IDN-5109 modulates Pgp activity by studying its effects on human carcinoma cells that express different amounts of Pgp. The authors found that Pgp-expressing cells accumulated and retained more IDN-5109 than paclitaxel and that IDN-5109 treatment caused such cells to retain higher levels of Pgp substrates than did treatment with paclitaxel. In vivo, intravenous or oral IDN-5109 treatment slowed the growth of Pgp-expressing tumors considerably more than paclitaxel. Combination treatment with the taxane-based Pgp modulator tRA96023 and IDN-5109 further enhanced therapeutic efficacy. The authors suggest that IDN-5109 and tRA96023 modulate Pgp activity by binding to Pgp and inhibiting the efflux activity of the pump.
PTEN, EGFR Alterations and Outcome in Glioma Patients
Survival of patients with anaplastic astrocytoma varies considerably. Because specific genetic alterations have been associated with glioblastoma, Smith et al. (p. 1246) tested tissue specimens from patients with anaplastic astrocytoma and from patients with glioblastoma multiforme for alterations of the EGFR, PTEN, and p53 genes and for copy number changes of chromosomes 7 and 10 to determine whether specific genetic alterations were associated with particularly aggressive anaplastic astrocytomas. They found that PTEN mutations appear to be important prognostic factors in patients with anaplastic astrocytoma and that EGFR amplification appears to be an important prognostic factor in older patients with glioblastoma multiforme.
Meta-analysis of Epoetin and Treatment-Associated Anemia
Anemia is a common side effect of chemotherapy for cancer. Although transfusion reverses anemia, it carries a small but real risk of infection. Erythropoietin, or epoetin, is a recombinant hormone used to treat anemia in other clinical settings, but there is controversy about the severity of anemia at which to start using it in cancer patients. In a meta-analysis, Seidenfeld et al. (p. 1204) analyzed published controlled trials to address the question of whether epoetin reduces the likelihood of transfusion or improves quality of life for patients undergoing cancer chemotherapy. The analysis evaluated outcomes separately for trials grouped by the patients’ initial severity of anemia. They found that, overall, epoetin reduced the risk of transfusion, but there was insufficient evidence that transfusions were reduced to a greater degree if treatment began when anemia was less severe. Evidence also was insufficient to establish that beginning treatment when anemia was less severe improved patients’ quality of life.
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