June 1 Clinical Cancer Research Highlights

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Selected Articles from the June 1, 2007 Issue

The articles referenced in this Highlights section will be available online in HTML and PDF formats to all interested users at no charge until the next issue of Clinical Cancer Research is published. Click on the article title to view the complete article.

View the Table of Contents for the June 1 issue of Clinical Cancer Research.

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CK18 Predicts Breast Cancer Treatment Efficacy Early 

Hägg Olofsson et al.
Page 3198

It is widely believed that accurate response biomarkers will help the pharmaceutical industry in making more rational go/no go decisions during the drug-development process. Hägg Olofsson et al. evaluated the use of the M30/M65 blood biomarker assays for assessment of patient response to anticancer drugs. M30 is specific for caspase-
cleaved CK18 produced by apoptotic cells, M65 for total CK18. CK18 biomarkers were found to be useful for early prediction of the response to cyclophosphamide/
epirubicin/5-fluorouracil (CEF) chemotherapy in breast cancer. Studies of the molecular form of CK18 in patient blood showed induction of necrotic cell death by anthracycline-
based therapy in several patients. Induction of necrosis in vivo may explain the clinical efficacy of CEF therapy for breast carcinomas with defective apoptosis pathways.

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KIF14 mRNA Expression Predicts Lung Cancer

Corson et al.
Page 3229

The mitotic kinesin KIF14 gene lies in a common region of genomic gain on chromosome 1 and is overexpressed in multiple cancers. Corson et al. show that expression of KIF14 is an independent prognostic factor in non-small-cell lung carcinoma. Moreover, they demonstrate that knockdown of KIF14 decreased cancer cell proliferation and growth in soft agar, the best in vitro predictor of tumorigenicity in vivo. These findings establish KIF14 as an important, novel oncogene and as a druggable ATPase specifically overexpressed in tumor cells, a very promising cancer therapeutic target.

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Body Composition Explains Variation in 5FU Chemotherapy Toxicity    

Prado et al.
Page 3264

Evidence suggests that lean body mass (LBM) may be useful to normalize doses of chemotherapy. Prado et al. used data from a prospective study to determine if the highest doses of 5-fluorouracil (5FU)/kg LBM would be associated with dose-limiting-
toxicity in stage II/III colon cancer patients treated with 5FU and leucovorin (5FU/LV). The authors demonstrated that low LBM is a significant predictor of toxicity in female patients administered 5FU using the convention of dosing per unit of body surface area. They concluded that variation in toxicity between females and males may be partially explained by this feature of body composition.

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Elacridar Improves Bioavailability of Oral Topotecan

Kuppens et al.
Page 3276

Breast cancer resistance protein (BCRP, ABCG2) substantially limits the oral bioavailability of topotecan. Coadministration with elacridar, an inhibitor of BCRP mediated drug transport, increases the bioavailability of topotecan. The aim of this study was to establish the lowest effective dose of elacridar to obtain maximum oral bioavailability of topotecan and to determine the optimal schedule of coadministration of oral topotecan and elacridar. Kuppens et al. concluded that the recommended schedule is 2.0 mg oral topotecan plus 100 mg elacridar administered concomitantly daily times five every 21 days. The strategy of combining oral topotecan and elacridar significantly improved the oral apparent bioavailability of topotecan from 40 to complete apparent bioavailability and may substantially improve the clinical application of topotecan.

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Microparticle Hydrophobic Infusion Delivers Paclitaxel Safely

Mita et al.
Page 3293

AI-850, paclitaxel in a novel polyoxyethylated castor oil-free hydrophobic microparticle delivery system, is being developed based on its favorable preclinical safety and antitumor activity profiles. Mita et al. assessed the feasibility and safety of administering AI-850 as a <30 minute intravenous infusion without premedication every 3 weeks; determined the maximum tolerated dose and the phase II recommended dose of AI–850; studied the pharmacokinetics of paclitaxel; and sought evidence of anticancer activity. The authors concluded that administering AI-850 via a brief infusion once every 3 weeks was feasible at doses up to 205 mg/m². The potential of AI-850 as an alternative to other approved paclitaxel formulations requires further clinical evaluation.

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