Other highlights in the July 7 JNCI

One purpose of a phase I clinical trial of a new cytotoxic drug is to determine the side effects associated with increasing drug dose, i.e., determine the dose that produces the maximum effect at which the toxicity can still be tolerated. New targeted, non-cytotoxic anticancer agents, such as small-molecule kinase inhibitors, pose challenges to this paradigm because they can achieve their maximum effect at levels lower than the maximum tolerated dose.

In a new study, Wendy R. Parulekar, M.D., and Elizabeth A. Eisenhauer, M.D., of Queen's University in Kingston, Ontario, reviewed endpoints used in 60 published phase I studies of targeted, non-cytotoxic anticancer agents. They found that the majority of studies used the traditional endpoint of toxicity to determine the recommended dose for the phase II trials. 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, Edward L. Korn, Ph.D., of the National Cancer Institute, discusses the assumptions and considerations required for choosing an endpoint in a phase I trial of a cytotoxic agent, and the challenges in using nontraditional endpoints for the dose selection of targeted, non-cytotoxic agents.

Contact: Wendy Parulekar, Queen's University, wparulekar@ctg.queensu.ca

Possible Targeted Therapy for Some Thyroid Cancers Identified

A new study identifies RPI-1, a Ret tyrosine kinase inhibitor, as a possible targeted therapy for the treatment of some thyroid cancers.

About 30% of medullary thyroid carcinomas are inherited, either as part of the multiple endocrine neoplasia type 2 (MEN2) syndromes MEN2A and MEN2B or the related disease, familial medullary thyroid carcinoma. Patients with medullary thyroid carcinoma can only be cured through surgery, which is only be performed before the cancer has metastasized clinically, as the cancer does not respond to standard chemotherapy or radiation.

Cinzia Lanzi, Ph.D., of the Istituto Nazionale Tumori in Milan, Italy, and colleagues tested the effects of the novel 2-indolinone RET tyrosine kinase inhibitor RPI-1 on a mouse model of MEN2A medullary thyroid carcinoma. When delivered orally, RPI-1 had a strong antitumor effect. The authors conclude that RPI-1's antitumor efficacy and oral bioavailability make it potentially useful to target Ret oncoproteins in humans.

In an editorial, Samuel A. Wells, M.D., and Joseph R. Nevins, Ph.D., of Duke University Medical Center in Durham, N.C., address potential strategies for targeted cancer therapy and discuss the importance of RET inhibitors to slow the growth of thyroid tumors.

Contact: Franco Zunino, Istituto Nazionale Tumori, 39-02-2390-2267, franco.zunino@istitutotumori.mi.it

Study Finds Possible Mechanism for Acrylamide's Mutagenicity

Acrylamide, a known rodent carcinogen, is found in many commonly consumed foods, including breakfast cereals, french fries, and potato chips. Although the mechanism by which acrylamide exerts its carcinogenic effect is unclear, acrylamide and its primary metabolite glycidamide are mutagenic. A new study reports a possible mechanism by which acrylamide mutates DNA and causes cancers.

Ahmad Besaratinia, Ph.D., and Gerd P. Pfeifer, Ph.D., of the City of Hope National Medical Center in Duarte, Calif., looked at the effects of acrylamide and glycidamide on specific genes in a mouse model and in normal human bronchial epithelial cells. They found that acrylamide and glycidamide could bind to the DNA, forming adducts, at similar specific locations in each of the genes studied. These adducts, which were more common when the cells were treated with glycidamide, coincided with the locations of specific gene mutations.

The authors conclude that acrylamide's mutagenicity is based on the ability of its metabolite glycidamide to form DNA adducts.

Contact: Greg Hughes, City of Hope National Medical Center, 626-359-8111 x65263, ghughes@coh.org

Death Pathway Genetic Polymorphisms Associated With Increased Risk of Esophageal Cancer

Abnormal regulation of apoptosis, or programmed cell death, can lead to many diseases, including cancer. In a new study, Dongxin Lin, M.D., of the Chinese Academy of Medical Sciences in Beijing, and colleagues find that genetic polymorphisms in two genes that play a role in apoptosis, FAS and FASL, are associated with an increased risk of developing esophageal squamous-cell carcinoma.

Contact: Ruoqi Xing, Chinese Academy of Medical Sciences, 8610-65105935, xingrq@ms.imicams.ac.cn

Also in the July 7 JNCI: