© 2004 by Oxford University Press
© 2004 Oxford University Press
IN THIS ISSUE |
Phase I Trial Design for Targeted, Non-Cytotoxic Agents
New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to the current phase I paradigm of dose selection based on toxicity. Parulekar and Eisenhauer (p. 990) reviewed strategies used in 60 completed phase I studies of 31 targeted drugs. The authors found that toxicity was the major endpoint used in the selection of the recommended phase II dose. Nontraditional endpoints, such as measures of molecular drug effects in tumor or surrogate tissue or functional imaging studies, were not routinely incorporated into the study design and rarely formed the primary basis for dose selection. The authors conclude that although phase I studies of targeted anticancer agents in general continue to use traditional endpoints for selection of the recommended phase II dose, suitable molecular measures of drug effect and the means to incorporate them in the early drug development process are needed to optimize dose selection and drug development strategies.
In an editorial, Korn (p. 977) discusses the assumptions and considerations required for choosing an endpoint in a phase I trial of a cytotoxic agent and how these relate to using nontraditional end-points for the dose selection of targeted, non-cytotoxic agents.
HPV and Head and Neck Cancer
High-risk human papillomaviruses (HPVs), particularly HPV type 16 (HPV16), are found in a subgroup of head and neck squamous-cell carcinomas (HNSCCs). HPV16-associated carcinogenesis is mediated by expression of the viral E6 and E7 oncoproteins, which inactivate the p53 and pRb pathways, respectively. Braakhuis et al. (p. 998) examined the genetic profiles of HNSCCs that contained or lacked transcriptionally active HPV. They found that none of the tumors that expressed HPV E6 or E7 had mutations in the gene encoding p53, whereas 75% of HPV DNA–negative tumors had such mutations. Moreover, HNSCCs that expressed HPV E6 and E7 had lower levels of allelic loss at chromosomal regions that contain tumor suppressor genes in the p53 and pRb pathways than HPV DNA–negative HNSCCs. The authors conclude that these distinct patterns of genetic alteration suggest that HPV16 infection is an early event in HNSCC development.
In an editorial, Mao and Hong (p. 978) note that these findings suggest that HPV16 oncoproteins E6 and E7 may play a role similar to those of the tumor suppressor genes located at the chromosomal regions that undergo loss in the HNSCCs. They discuss the notion that transcriptionally active HPV16 is required in a subset of HNSCCs to maintain the malignant phenotype.
Antitumor Activity of RPI-1 on Medullary Thyroid Carcinoma
Ret oncoproteins are constitutively active tyrosine kinases involved in the etiopathogenesis of medullary thyroid carcinoma, a cancer that responds poorly to chemotherapy. Cuccuru et al. (p. 1006) investigated the antiproliferative and antitumor effects of the RET inhibitor RPI-1 on human medullary carcinoma cells that express the RET oncogene. Through inhibition of kinase activity and Ret expression, RPI-1 blocked RET oncogene-dependent cellular proliferation, transformation, and tumor formation in mice. The authors conclude that RPI-1's antitumor efficacy and oral bioavailability make it potentially useful to target Ret oncoproteins in humans.
In a related editorial (p. 980), Wells and Nevins address potential strategies for targeted cancer therapy. They discuss the importance of RET inhibitors to slow the growth of thyroid tumors resistant to traditional chemotherapy and radiotherapy, and they suggest targeting multiple signal transduction pathways to slow the growth of highly malignant, drug-resistant tumors.
Dairy Foods, Calcium, and Colorectal Cancer
Studies in animals have suggested that calcium may reduce the risk of colorectal cancer. However, results from epidemiologic studies of intake of calcium or dairy foods and colorectal cancer risk have been inconclusive. Cho et al. (p. 1015) pooled the primary data from 10 cohort studies in five countries that assessed usual dietary intake by using a validated food frequency questionnaire at baseline. The authors found that milk and calcium intakes were associated with a reduced risk of colorectal cancer and that the results were consistent across studies and sex. The inverse association for milk was limited to cancers of the distal colon and rectum. The authors conclude that a higher consumption of milk and calcium is associated with a reduced risk of colorectal cancer.
Acrylamide and Glycidamide Genotoxicity
Acrylamide is a proven rodent carcinogen that exists in the human diet. The mechanism by which acrylamide exerts its carcinogenic effects is unclear. However, both acrylamide and its primary epoxide metabolite glycidamide are mutagenic. Besaratinia and Pfeifer (p. 1023) examined the mutagenic effects of acrylamide and glycidamide in normal human bronchial epithelial cells (a known target cell type for acrylamide-induced tumorigenesis) and transgenic mouse embryonic fibroblasts by mapping the formation of DNA adducts in the human TP53 gene and in a cII transgene. They found that acrylamide and glycidamide formed DNA adducts at similar specific locations in each gene, DNA-adduct formation was more pronounced after glycidamide treatment than after acrylamide treatment, glycidamide treatment increased the frequency of cII mutations in a dose-dependent manner relative to control treatment, and glycidamide was more mutagenic than acrylamide.
FAS and FASL Polymorphisms and Esophageal Carcinoma
The FAS receptor and its ligand FASL form a key regulatory system for apoptotic cell death. Loss of FAS expression and gain of FASL expression play important roles in cancer development and progression. Sun et al. (p. 1030) examined the association between three functional polymorphisms in these genes and the risk of development and metastasis of esophageal squamous-cell carcinoma. They observed that an increased risk of esophageal squamous-cell carcinoma was associated with all three polymorphisms. They also found that the presence of more than one of these polymorphisms increased the risk of esophageal squamous-cell carcinoma in a multiplicative manner and that tobacco smoking increased this risk even further. They conclude that these results support the hypothesis that the FAS- and FASL-triggered apoptosis pathway plays an important role in human carcinogenesis.
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