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View the Table of Contents for the June 15 issue of Clinical Cancer Research.
Gururaja et al. Page 3831
Loss of clinical efficacy of many useful microtubule targeting drugs because of resistance and undesired side effects necessitates development of new tubulin-binding chemical entities that are devoid of such activities. Gururaja et al. used a proprietary high-content cell-based screen of a compound library to identify R-253 [N-cyclopropyl-2-(6-(3,5-dimethylphenyl)thieno[3,2-d]pyrimidin-4-yl)hydrazine carbothioamide], a potent anti-proliferative agent (average EC50 = 20 mol/L). R-253 emerged from the library as effective when assessed for growth, cytotoxicity, apoptosis, and cell cycle progression in a spectrum of tumor cell lines, including cells that were resistant to known microtubule inhibitors. Both biochemical and cellular mechanistic studies indicate that R-253 could become a promising new tubulin-binding drug candidate for treating various malignancies.
Kelloff et al. Page 3661
This article from the AACR Cancer Prevention Task Force reviews emerging concepts in chemopreventive drug development. Molecular biomarker expressions in carcinogenesis and genetic progression models of intraepithelial neoplasia are emphasized. Their roles in mechanism-based, molecular-targeted drug development, risk stratification, and cohort and endpoint selection for clinical trials are analyzed. Updates on ten clinical target organs include new data on molecular progression, significant trials, agents, and promising directions for future studies. Strategies for accelerating chemopreventive drug development are discussed, such as integrating new science into clinical development planning and regulatory policy, providing industry incentives, fostering multisector cooperation, and educating the public.
Page 3843
The substance P receptor neurokinin type 1 is overexpressed in the vast majority of malignant glial brain tumors. Kneifel et al. developed a new 1806 Da targeting vector by conjugating the chelator DOTAGA to substance P, which specifically targets tumor cells. In a pilot study, feasibility, biodistribution, and early and long-term toxicity were assessed in 20 brain tumor patients following direct intratumoral administration. Disease was stabilized and neurologic status improved in 13 of 20 patients. Secondary resection disclosed widespread radiation necrosis with improved demarcation. Targeted radiotherapy using diffusible peptidic vectors represents an innovative strategy for local control of malignant gliomas.