© 1999 by Oxford University Press
Journal of the National Cancer Institute, Vol. 91, No. 5, 395,
March 3, 1999
© 1999 Oxford University Press
IN THIS ISSUE |
Resistance of cancer cells to many anticancer drugs is known to be mediated by P-glycoprotein and multidrug resistance-associated protein (MRP), which are members of the adenosine triphosphate-binding cassette (ABC) superfamily of transporter proteins. However, cancer cells exhibiting resistance to the drug mitoxantrone frequently do not overex-press these proteins. Ross et al. (p. 429) studied expression of the messenger RNA (mRNA) for a recently described member of the ABC transporter family, i.e., breast cancer resistance protein (BCRP), in a variety of mitoxantrone-selected cancer cell lines and found that BCRP mRNA is overexpressed in most of them. This finding suggests that overexpresssion of BCRP may represent a major cellular defense mechanism that is induced in response to mitoxantrone exposure.
Biennial Colorectal Cancer Screening
Mandel et al. (p. 434) update their randomized Minnesota trial of colorectal cancer screening comparing outcome among groups receiving annual fecal occult blood tests (FOBT) or biennial FOBT and control subjects given usual medical care through 18 years of follow-up. They report that the biennial screening group had a 21% lower colorectal cancer mortality than the control group. The authors say that these updated results, together with the results of two other previously published randomized trials of fecal occult blood screening, are now consistent in demonstrating substantial, statistically significant colorectal cancer mortality reductions (15%-21%) from biennial screening.
In an accompanying editorial, Levin (p. 399) discusses the evidence supporting the effectiveness of fecal occult blood testing in screening for colorectal cancer. The finding of beneficial effects of screening every 2 years is of considerable public health importance, Levin says, and confirms the findings of the other two randomized, controlled trials. Screening of men and women aged 50 years and older can save many lives, he notes.
Fetal Exposure to Cigarette Carcinogens
Expectant mothers who smoke cigarettes pass a potent tobacco-specific carcinogen across the placental barrier to the developing fetus, according to a study by Lackmann et al. (p. 459). The investigators analyzed the first urine samples from newborns whose mothers did or did not smoke for metabolites of the carcinogen called NNK. They found at least one NNK metabolite present in the urine of 71% of newborns of smoking mothers— and none at all in the urine of newborns of nonsmoking mothers.
Analyzing Microarray Data
Complementary DNA (cDNA) array technology provides large amounts of data on gene expression, but there are no well-established and widely accepted standards to guide the analysis and interpretation of the data generated. To this end, Hilsenbeck et al. (p. 453) have explored principal components analysis. They report that this method can identify genes with altered expression in a mouse model of acquired tamoxifen resistance. In this model, human breast cancer cell tumors undergo three stages of growth. For each tumor type, the authors analyzed cDNAs, made from RNA isolated from the tumor, on a microarray. They selected two representative outlier genes whose protein expression also appeared to be altered. The authors conclude that principal components analysis provides a useful and practical method to analyze gene expression data from cDNA arrays and that this method should be able to identify broad patterns of alterations in gene expression in clinically important genes.
In an editorial, Wittes and Friedman (p. 400) discuss the methodology used by Hilsenbeck et al. to assess gene expression. The editorial writers evaluate the analytical methods chosen and the assumptions made. They point out that new problems need exploration by many methods to gain insight into the data and the relationships of interest. Wittes and Friedman encourage people interested in these problems to share data from experiments, such as the one described by Hilsenbeck et al., to stimulate methodologic research.
Interleukin-4 Gene Therapy for Glioma
Gliomas, the most common primary brain tumors in humans, are difficult to treat successfully. The cytokine inter-leukin 4 (IL-4) exhibits antitumorigenic activity in immunodeficient nude mice by promoting eosinophil infiltration and inhibiting the formation of new blood vessels in tumors. Saleh et al. (p. 438) therefore investigated whether injecting packaging cells transfected with a retroviral vector encoding mouse IL-4 into experimental rat glioma cell tumors could stop or reverse tumor growth. The researchers found that injection of such cells into established rat gliomas grown subcutaneously in nude mice arrested tumor growth and that the packaging cells were effective in dramatically reducing the size of gliomas established in the brains of immunocompetent rats. Furthermore, the IL-4-retrovirus-packaging cells provided sustained protection against formation of tumors when glioma cells were again injected in the treated rats' brains.
CDKN2A and Melanoma Risk
Mutations in CDKN2A, a gene that encodes an inhibitor of a cell-cycle regulatory enzyme, are associated with susceptibility to cutaneous malignant melanoma (CMM). To determine the possible role of variants in this gene—mutations and sequence polymorphisms—in altering the risk of familial melanoma, Aitken et al. (p. 446) examined DNA from members of 482 Australian families previously characterized as having high, intermediate, or low family risk of CMM and of individuals from another 200 families who served as controls. The researchers found CDKN2A mutations in members of nine of 87 high-risk families but not in subjects from intermediate- or low-risk families or from the control population. Prevalence of a CDKN2A polymorphism with guanine at nucleotide 500 (Nt500G) increased linearly with increasing familial risk, but the association probably reflects the greater number of families of Celtic ancestry in the high-risk group, the researchers suggest.
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