© 2005 Oxford University Press
IN THIS ISSUE
Lifetime Risk of Melanoma in CDKN2A Mutation CarriersPrevious reports indicate that lifetime risk of melanoma in CDKN2A mutation carriers is high among people in multiple-case families. Begg et al. (p. 1507) calculated lifetime melanoma risk using the kin–cohort method in 65 CDKN2A mutation carriers who were identified among 3550 probands, case patients with either first or subsequent melanoma, in a population-based study. The authors found that melanoma risk in the carriers was approximately 14% by age 50 years, 24% by age 70 years, and 28% by age 80 years. They conclude that lifetime melanoma risk in CDKN2A mutation carriers in the general population is much lower than that suggested by estimates derived from studies of multiple-case families and that clustering of melanoma occurs in families without identifiable CDKN2A mutations.
In an editorial, Goldstein and Tucker (p. 1486) compare the results and population-based design of the study by Begg et al. with those from studies of multiple-case families and conclude that the results of Begg et al. are not surprising given that other melanoma risk factors may also cluster among multiple-case families. They state that it is premature to consider widespread testing for CDKN2A mutations and that further research should provide additional information to better understand melanoma.
Early Complications After Radical Prostatectomy
Radical prostatectomy is associated with excellent long-term disease control for localized prostate cancer but also with substantial potential morbidity and mortality. Many clinicians consider older men to be at higher risk of surgery-associated short-term and long-term complications, and men ages 70 and older are unlikely to undergo this procedure. To investigate whether mortality and complications occurring within 30 days following radical prostatectomy are associated with age, Alibhai et al. (p. 1525) analyzed data on 11 010 men who underwent this surgery in Ontario between 1990 and 1999, adjusting for comorbid conditions. Although age was associated with increased risk of 30-day mortality, the absolute mortality risk was low, even in older men. Age was also associated with an increased risk of cardiac, respiratory, and other medical complications. The authors conclude that risk of post-operative complications after radical prostatectomy is relatively low for otherwise healthy older men.
Targeted Immunotherapy and Photodynamic Therapy
Epithelial ovarian cancer often develops resistance to standard treatments. del Carmen et al. (p. 1516) tested the efficacy of a combination treatment regimen consisting of C225, a monoclonal antibody that inhibits the receptor tyrosine kinase activity of epidermal growth factor receptor (EGFR), and benzoporphyrin derivative monoacid A (BPD)-based photodynamic therapy (PDT) in a mouse model of human ovarian cancer. Mice treated with PDT+C225 had a substantial reduction in mean tumor burden to 9.8% of that of no-treatment control mice, whereas mice treated with C225 only or PDT only had mean tumor burdens of 66.6% and 38.2%, respectively. When compared with PDT only or C225 only, PDT+C225 produced synergistic reductions in mean tumor burden and improvements in survival. The authors conclude that a mechanistically nonoverlapping combination regimen involving photochemistry-based BPD-PDT and C225-mediated receptor tyrosine kinase inhibition is well-tolerated, effective, and synergistic in a murine model for ovarian carcinomatosis.
In an editorial, Cengel et al. (p. 1488) discuss the theoretical advantages of using C225 and PDT to exploit different aspects of ovarian carcinoma tumor biology, explore mechanistic reasons why interactions between EGFR signaling and PDT could be complex, and note that analyzing the efficacy and molecular profiles of responders and nonresponders in clinical trials may be as valuable as analyzing potential mechanisms and targets of a new therapy in preclinical model systems.
Trial of Combination Chemo for Unresectable HCC
Hepatocellular carcinoma (HCC) is highly aggressive; only 10%–20% of patients are candidates for curative surgery. Single-agent doxorubicin has been widely used to treat unresectable HCC, but there is no convincing evidence for improved survival. Yeo et al. (p. 1532) report the results of a randomized trial in which patients with unresectable HCC were randomly assigned to receive either doxorubicin or cisplatin, interferon, doxorubicin, and fluorouracil (PIAF) in combination. Although a higher overall response rate and improved survival were observed among patients who received PIAF compared with patients on doxorubicin, the differences were not statistically significant. PIAF was also associated with increased treatment-related toxicity.
Using Yeast to Study Resistance to an Angiogenesis Inhibitor
Identifying pathways that mediate cellular responses to drugs is key to understanding drug action and selectivity. In this issue, Dilda et al. (p. 1539) identified mammalian components of the response to the synthetic tripeptide arsenical compound GSAO, an angiogenesis inhibitor that targets mitochondria and to which tumor cells display more resistance than normal endothelial cells. The authors began by screening a genome-wide set of yeast deletion strains for GSAO-sensitive strains. Many of the genes that were deleted in the sensitive yeast strains are involved in glutathione synthesis or vacuolar function. The authors then treated mammalian cells with modulators of analogous mammalian cell processes (i.e., glutathione synthesis and multidrug resistance protein [MRP] activity) and found that GSAO responses were disrupted, indicating that these processes also mediate GSAO responses in mammalian cells. The authors suggest that MRP may transport GSAO from resistant cells, with glutathione acting as a cotransporter.
DNA Methyltransferase Inhibitors as Cancer Therapies
In a review, Lyko and Brown (p. 1498) examine the literature on DNA methyltransferase inhibitors and discuss the effectiveness of these compounds as antitumor agents in phase I–III clinical trials. They point out that, unlike DNA mutations, epigenetic mutations are reversible and that this reversibility provides the foundation for the use of small molecule inhibitors in novel cancer strategies. They conclude by pointing out areas for future research and emphasizing the need to develop assays for genome-wide and tumorspecific DNA methylation so that pharmacodynamic parameters of DNA methyltransferase inhibitors can be established to maximize the therapeutic efficacy of these compounds.
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