© 2002 by Oxford University Press
Journal of the National Cancer Institute, Vol. 94, No. 2, 77,
January 16, 2002
© 2002 Oxford University Press
IN THIS ISSUE |
Dunstan et al. (p. 88) have developed a cell-based assay to identify anticancer agents that are selectively toxic to cells with defined mutations. They used this assay to identify agents in the National Cancer Institute’s repository of compounds that are selectively toxic to yeast cells deficient in DNA double-strand break repair. They identified and characterized eight agents that are selectively toxic to such yeast cells: two novel topoisomerase II poisons, five agents with topoisomerase I-dependent toxicity, and one agent that bound to DNA and induced strand breaks. They concluded that cell-based assays can be used to identify molecules that are selectively toxic to cells with a predetermined genetic background.
In an accompanying editorial, Balis (p. 78) notes that cell-based screening assays for new anticancer drugs will play an important role in drug discovery in the molecular-targeting era. Target-based and new cell-based screening assays such as the one reported by Dunstan et al. are complementary and represent a dramatic shift in the drug discovery process. This shift may influence pharmacological properties of new anticancer agents reaching the clinic, the approach to clinical drug development, and the treatment of cancer.
DNA Repair and Malignant Melanoma
The incidence of cutaneous malignant melanoma (CMM) and mortality from this disease in Caucasians have increased rapidly throughout the world in recent decades. Exposure to UV radiation is associated with CMM. In mammalian cells, UV radiation induces DNA damage that can be repaired by the nucleotide excision repair system. In a case–control study, Landi et al. (p. 94) investigated whether DNA repair capacity (DRC) was associated with increased risk of CMM. They found no statistically significant association between melanoma risk and DRC by itself. However, they observed that DRC strongly influenced CMM risk in individuals with a low tanning ability or dysplastic nevi. The authors conclude that, as with all statistical interactions, replication in an independent study is necessary.
Age and HPV testing for Cervical Cancer Screening
Approximately 5% of women with atypical squamous cells of undetermined significance (ASCUS) and 10% of women with low-grade squamous intraepithelial lesions (LSIL) on their Pap test are found to have cervical intraepithelial neoplasia 3 (CIN3). In an analysis of the ASCUS LSIL Triage Study (ALTS), Sherman et al. (p. 102) examined whether age or viral load affects the performance of testing for oncogenic human papillomavirus (HPV) DNA, a promising approach for managing women with ASCUS Pap tests. Among all women with ASCUS, HPV testing was highly sensitive in identifying patients with underlying CIN3. Among women aged 29 years and older with ASCUS, HPV testing would have referred many fewer patients for colposcopy than repeat cytopathology, and it also would have referred fewer patients than either triage technique in younger women. The authors also found that increasing the HPV testing threshold decreased colposcopy referrals, but the sensitivity for detecting CIN3 was reduced. Neither HPV testing nor repeat cytopathology provided useful management for women with LSIL.
Ethnic Differences in Nicotine Intake and Metabolism
The prevalence of lung cancer varies among ethnic groups: Asians and Latinos have a lower incidence of lung cancer than whites, and African-Americans have the highest incidence. To investigate possible reasons for some of these differences, Benowitz et al. (p. 108) compared nicotine intake per cigarette and nicotine metabolic rates among Chinese-American, Latino, and white smokers. Latinos and whites had similar nicotine metabolic rates and took in similar amounts of nicotine per cigarette, whereas Chinese-Americans metabolized nicotine more slowly and took in less nicotine per cigarette. Among all participants, nicotine metabolic rate and nicotine intake were positively correlated. The authors suggest that, because Chinese-Americans metabolize nicotine more slowly than whites, they may need to smoke fewer cigarettes to obtain the same nicotine levels, resulting in lower lung cancer incidence. They also note that differences in nicotine metabolism among ethnic groups may have implications for selecting doses of the nicotine medications used to aid smoking cessation.
Prognostic Value of uPA and PAI-1 in Breast Cancer
Urokinase-type plasminogen activator (uPA) and its inhibitor (PAI-1) play essential roles in tumor invasion and metastasis. High levels of both uPA and PAI-1 are associated with poor prognosis in breast cancer patients. To confirm the prognostic value of uPA and PAI-1 in primary breast cancer, Look et al. (p. 116) reanalyzed individual patient data from more than 8,000 primary breast cancer tumors collected by members of the European Organization for Research and Treatment of Cancer–Receptor and Biomarker Group. This pooled analysis of the datasets confirmed the strong and independent prognostic value of uPA and PAI-1 in primary breast cancer. High levels of uPA and PAI-1, apart from lymph node status, were the strongest predictors of poor relapse-free survival of patients. The authors point out that, for patients with lymph node-negative breast cancer, uPA and PAI-1 measurements in primary tumors may be especially useful for designing individualized treatment strategies.
pRB and Pancreatic Cancer
Pancreatic cancers are often resistant to chemotherapy-induced apoptosis. The p16 tumor suppressor protein is inactivated in more than 90% of pancreatic cancers, possibly because it is transcriptionally inhibited by the retinoblastoma tumor suppressor protein pRB. pRB expression is, however, transcriptionally inhibited by p16. Because pRB prevents apoptosis and pRB expression is inversely related to p16 expression, Plath et al. (p. 129) hypothesized that re-expression of p16 in pancreatic cancer cells should decrease resistance to chemotherapy-induced apoptosis. The authors found that, when p16 was expressed in pancreatic cancer cell lines, pRB expression and activity decreased and chemotherapy-induced apoptosis increased. The authors conclude that overexpression of pRB, which is associated with human pancreatic ductal adenocarcinomas, may allow pancreatic cancer cells to evade chemotherapy-induced apoptosis.
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