© 2001 by Oxford University Press
Journal of the National Cancer Institute, Vol. 93, No. 6, 411,
March 21, 2001
© 2001 Oxford University Press
IN THIS ISSUE |
Highly sensitive and specific biomarkers are attractive candidates for cancer screening programs. Hemstreet et al. (p. 427) used a panel of three predefined biomarkers (DNA ploidy, the bladder cancer antigen p300, and G-actin) to establish whether a profile based on these biomarkers could serve as a basis for risk stratification for bladder cancer in a longitudinal study of asymptomatic individuals in a Chinese cohort occupationally exposed to benzidine. The authors found that the risk of developing bladder cancer was approximately 19 times higher for workers if either DNA ploidy or p300 was positive than workers negative for both markers, but 81 times higher for workers when both the markers for DNA ploidy and p300 were positive. Nearly 90% of workers who developed bladder cancers were correctly stratified for more intensive screening. The authors conclude that occupationally exposed workers at risk for bladder cancer can be individually stratified and screened based on predefined biomarker profiles.
In an editorial (p. 413), Gazdar and Czerniak focus on the pathology, biology, and natural history of bladder cancer to discuss the advantages of risk assessment and early detection studies that use urinary markers and biomarkers.
Small Molecule Inhibitor of Cdk4
Cyclin-dependent kinase 4 (Cdk4) initiates phosphorylation of the retinoblastoma protein (pRb), which ultimately causes cells to proliferate. Cdk4 is aberrantly activated in many human tumors, making this enzyme an important therapeutic target in cancer. Soni et al. (p. 436) tested a triaminopyrimidine derivative that can inhibit Cdk4 enzyme activity in vitro, CINK4 (Chemical INhibitor of CdK4), for its effects on cell growth and tumor volume in vivo. The authors found that, in vitro, CINK4 specifically inhibited Cdk4 complexed with cyclin D1 and that, in cultured cells, it prevented pRb phosphorylation and caused a profound growth arrest in tumor cells that lack p16, a natural inhibitor of Cdk4. In vivo, CINK4 treatment slowed tumor growth in a mouse xenograft model. The authors suggest that these effects of CINK4 are a consequence of Cdk4 inhibition.
In an accompanying editorial, Kubo and Kaye (p. 415) review the features of the retinoblastoma/p16 tumor suppressor pathway that make it an attractive target for novel cancer treatment strategies. However, they caution that potential inhibitors of this pathway should undergo rigorous preclinical characterization before they can be prioritized for clinical studies.
Costs of Breast-Conserving Therapy and Mastectomy
Women choosing treatment for early-stage breast cancer must weigh many factors, possibly including treatment costs. To compare the costs of breast-conserving therapy (BCT) and mastectomy, Barlow et al. (p. 447) evaluated medical care costs for women with breast cancer enrolled in a large, regional nonprofit health maintenance organization. Treatment costs were determined for women who received BCT plus radiation therapy, BCT plus radiation therapy plus adjuvant therapy, mastectomy, or mastectomy plus adjuvant therapy. Treatment costs 6 months after diagnosis were higher for both BCT groups than for both mastectomy groups. After 1 year, costs for BCT and mastectomy were similar. After 5 years, costs for both BCT groups were lower than those for both mastectomy groups. The authors note that, overall, the costs of BCT and mastectomy are similar, and they suggest that treatment costs should play little role in a woman’s decision about how to treat early-stage breast cancer.
15-Year Update of the Scottish Tamoxifen Trial
The Scottish Adjuvant Tamoxifen Trial was initiated in April 1978 to assess the effect of tamoxifen given to patients with breast cancer immediately after mastectomy (adjuvant arm) or only after the patient had a relapse (control arm). A duration trial was initiated at 5 years for patients in the adjuvant arm of the main trial, who, if agreeable and eligible, were randomly assigned to stop taking tamoxifen or to continue taking it indefinitely until relapse or death. After a median follow-up of 15 years, Stewart et al. (p. 456) report that the beneficial effects of adjuvant tamoxifen given for 5 years were maintained, but no additional benefit was observed in those who continued taking tamoxifen beyond 5 years. The authors conclude that, based on present evidence, adjuvant tamoxifen need not be given for more than 5 years to women with operable breast cancer.
Antitumor Activity of an Antisense Oligonucleotide
Apoptosis, or programmed cell death, is a normal function of cells that may help prevent cancer development. The Bcl-2 family of proteins is involved in the control of apoptosis; overexpression of the proteins is associated with reduced apoptosis in solid tumors. Gautschi et al. (p. 463) hypothesized that simultaneous inhibition of two closely related genes, bcl-2 and bcl-xL, might allow apoptosis to proceed. They tested this idea by treating cell lines from a variety of tumors with antisense oligonucleotide 4625, which was designed to act against both of the genes. They found that oligonucleotide 4625 reduced both transcription and protein expression from the two genes and resulted in resumption of apoptosis in the cells tested. In mice, the oligonucleotide inhibited the growth of transplanted breast and colorectal tumors, with concurrent decreased bcl-2 and bcl-xL protein levels. The authors conclude that the bispecific activity of oligonucleotide 4625 against two anti-apoptosis genes holds promise for therapeutic applications.
Gene Therapy in Woodchucks for Hepatocellular Carcinoma
Cytokine-based gene therapy efficiently stimulates immune responses against many types of established transplanted tumors, leading to rejection of the tumor. Pützer et al. (p. 472) tested cytokine-based gene therapy in woodchucks with primary hepatocellular carcinomas by using AdIL-12/B7.1, an adenovirus vector carrying genes for murine interleukin 12 and B7.1. One to two weeks after tumors were injected with AdIL-12/B7.1, the authors observed substantial tumor regression accompanied by massive T-lymphocyte infiltration and increased levels of CD4+ and CD8+ T cells and interferon gamma, compared with tumors injected with a control vector. When a tumor injected with AdIL-12/B7.1 was followed for 7 weeks, the authors observed a 95% or more reduction in the size of the tumor compared with its size before treatment. Thus, the authors conclude that adenovirus vector-based immunotherapy appears to be an effective treatment of large nontransplanted tumors.
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