Clin Cancer Res
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Review Randomized Controlled Trial Clinical Trial
Follow-up of the breast cancer prevention trial and the future of breast cancer prevention efforts.
Women who are at increased risk for developing breast cancer can be identified using quantitative risk assessment models that provide valid estimates of risk. The Breast Cancer Prevention Trial (BCPT, P-1) demonstrated that tamoxifen can reduce the incidence of both invasive and noninvasive breast cancer as well as of bone fractures in women at increased risk. These benefits accrue at the expense of increased risk of endometrial cancer, thromboses, cataracts, and possibly diminished quality of life in postmenopausal women. ⋯ Thromboembolic events and endometrial cancer are the predicted toxicities. Ancillary studies of cognitive function will also be performed. Raloxifene should not be used for the reduction of breast cancer risk outside the context of the STAR trial.
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Clinical Trial
Phase I study of topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as weekly 24-hour infusions three of every four weeks.
Exatecan mesylate (DX-8951f) is a topoisomerase I inhibitor that has increased solubility and antitumor activity compared with other topoisomerase I inhibitors. The purpose of this study was to establish a safe dose of DX-8951f given as a weekly 24-h infusion 3 of every 4 weeks. DX-8951f was administered as a 24-h continuous infusion in escalating doses. ⋯ Nonhematological toxicities were mild and consisted of mild diarrhea, asthenia, mild nausea, and constipation. Pharmacokinetic parameters could be well described with a one-compartment model in most patients, although the application of the one-compartment model probably resulted in an underestimated elimination half-life. In conclusion, the recommended Phase II dose for DX-8951f administered as a weekly 24-h infusion on a 3-of-4 week schedule is 0.8 mg/m(2) in minimally pretreated patients and 0.53 mg/m(2) in patients who are heavily pretreated.
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Clusterin expression is highly up-regulated in several normal and malignant tissues undergoing apoptosis. Although recent studies have demonstrated a protective role of clusterin expression against various kinds of apoptotic stimuli, the functional role of clusterin in the acquisition of a therapy-resistant phenotype in bladder cancer remains unknown. The objectives of this study were to determine whether antisense (AS) oligodeoxynucleotide (ODN) targeting the clusterin gene enhances apoptosis induced by cisplatin and to evaluate the usefulness of combined treatment with AS clusterin ODN and cisplatin in the inhibition of KoTCC-1 tumor growth and metastasis in a human bladder cancer KoTCC-1 model. ⋯ KoTCC-1 tumor volume compared with mismatch control ODN plus cisplatin. Furthermore, after the orthotopic implantation of KoTCC-1 cells, combined treatment with AS clusterin and cisplatin significantly inhibited the growth of primary KoTCC-1 tumors, as well as the incidence of lymph node metastasis. Collectively, these findings demonstrated that clusterin helps confer a chemoresistant phenotype through inhibition of apoptosis and that combined AS clusterin ODN may be useful in enhancing the effects of cytotoxic chemotherapy in patients with bladder cancer.
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A Phase I study of exatecan, a new water-soluble camptothecin derivative, was conducted to determine the maximum tolerated dose and a recommended dose, according to an internationally standardized core protocol. Pharmacological profiles of lactone and total (lactone + carboxylate) exatecan were also investigated. ⋯ The recommended dose of exatecan infused over 30 min every 3 weeks is 5 mg/m(2), with a favorable toxicity profile of mild and infrequent diarrhea. Interpatient variability of pharmacokinetics was similar to or smaller than that with other camptothecin derivatives.
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Overexpression of the Her-2/neu oncogene and receptor protein was reported in approximately 20% of breast cancers and was associated with a poor prognosis. Her-2/neu expression was a predictor for response to trastuzumab, a monoclonal antibody that recognizes the Her-2/neu cell surface receptor. Data regarding the expression of Her-2/neu in lung cancer are far more limited, and there is little information regarding the influence of Her-2/neu expression and response to trastuzumab alone or in combination with chemotherapeutic agents. ⋯ The IC(50) for growth inhibition was correlated with cell surface Her-2/neu expression. The combination of trastuzumab and chemotherapeutic agents produced more than additive growth inhibition in cell lines expressing Her-2/neu, but the level of additivity was not related to the amount of Her-2/neu expression. These data indicate that trastuzumab alone and in combination with chemotherapeutic agents should be tested in NSCLC patients and that Her-2/neu should be assessed by both immunohistochemistry and FISH methods in these studies to determine which test is the best predictor of outcome.