Clin Cancer Res
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Platinum-based chemotherapeutic agents, such as carboplatin and cisplatin, are effective against many human tumors, but their use may be limited by a high incidence of ototoxicity. Delayed administration of the chemoprotective agent sodium thiosulfate (STS) reduces the ototoxicity of carboplatin in a guinea-pig model, when given up to 8 h after the chemotherapy, and also reduces hearing loss in patients given carboplatin with osmotic blood-brain barrier opening for treatment of brain tumors. We tested whether STS, given at times that achieved otoprotection, could impact the chemotherapeutic efficacy of carboplatin. ⋯ To explore the potential wider applicability of STS, in a pilot study we tested its efficacy against cisplatin ototoxicity. Delayed administration of STS, 2 h after cisplatin, was protective against cisplatin-induced ototoxicity in the guinea pig model, as determined by electrophysiological measures. On the basis of these data, we suggest that delayed administration of STS may provide a mechanism to reduce the ototoxicity caused by administration of carboplatin or cisplatin for both central nervous system and systemic cancer chemotherapy.
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We have established two metastatic models of human non-small cell lung carcinoma (NSCLC)-the NCI-H460 large-cell carcinoma and the A549 adenocarcinoma-by inoculating tumor cells into the pleural space of nude mice. The objectives of this work were as follows: (a) to study the histological characteristics and growth and dissemination patterns of these tumors in nude mice; (b) to assess their sensitivity to drugs that have demonstrated significant clinical therapeutic effect in the treatment of NSCLC; and (c) to investigate the antitumor activity of S 16020-2, a new olivacine derivative, currently in Phase II clinical evaluation. In each of the two models, all animals developed lung tumors, resulting in 100% mortality. ⋯ However, none of these drugs was curative, reflecting the resistance of this disease to chemotherapy. S 16020-2 exhibited a remarkable antitumor activity, increasing the survival by 82% (P < or = 0.01) for NCI-H460 and by 126% (P < or = 0.001) for A549. This drug was among the most active compounds in these models, thereby indicating its potential for the chemotherapy of this disease.
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Multicenter Study Comparative Study Clinical Trial
Phase I study of topotecan administered as a 21-day continous infusion in children with recurrent solid tumors: a report from the Children's Cancer Group.
The purpose of this study was to determine the toxicity, maximum tolerated dose, and pharmacokinetics of a 21-day continuous infusion of topotecan in children with relapsed solid tumors. Fifteen patients received 40 courses of continuous ambulatory infusions of topotecan every 28 days or when there was resolution of hematological toxicity and any grade 2 or greater nonhematological toxicity. The starting dose was 0.4 mg/m2/day. ⋯ Thus, a 21-day topotecan infusion was well-tolerated at 0.3 mg/m2/day. Myelo-suppression was the dose-limiting toxicity at 0.4 mg/m2/day. The steady state and clearance of topotecan in this study are similar to those reported in adult patients.
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Comparative Study
Hematogenous dissemination of hepatocytes and tumor cells after surgical resection of hepatocellular carcinoma: a quantitative analysis.
The only hope of long-term survival for patients with hepatocellular carcinoma (HCC) is surgical resection or liver transplantation. However, recurrence or metastasis formation is common after surgery. We aim to assess whether surgical resection leads to hematogenous dissemination of malignant and nontumor hepatocytes and determine the quantity and timing of hepatocyte shedding into the circulation. ⋯ The absence/clearance of afp mRNA in 75 % (six of eight) of survivors was strongly associated with the absence of metastasis/recurrence (P = 0.02). We present evidence that alb-expressing hepatocytes are released intraoperatively into the circulation, and afp-expressing tumor cells are disseminated mostly postoperatively that may potentially be the source of recurrence or metastasis. Sequential quantification of both alb and afp mRNAs may provide insights for risk assessment and prognostic indication.
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Clinical Trial
c-raf-1 depletion and tumor responses in patients treated with the c-raf-1 antisense oligodeoxynucleotide ISIS 5132 (CGP 69846A).
Abnormally regulated signaling through proliferative signal transduction pathways characterizes many of the common solid tumors. The best described of these involves potentially oncogenic proteins of the Ras family, which activate Raf proteins in the early steps of the mitogen-activated protein kinase cascade. ISIS 5132, a phosphorothioate antisense oligodexoynucleotide directed to the 3' untranslated region of the c-raf-1 mRNA, inhibits the growth of human tumor cell lines in vitro and in vivo in association with specific down-regulation of target message expression. ⋯ We observed significant reductions of c-raf-1 expression from baseline by day 3 in 13 of 14 patients (P = 0.002). The time course and depletion of c-raf-1 message in peripheral blood mononuclear cells paralleled the clinical benefit in two patients. These findings demonstrate that ISIS 5132 specifically reduces target gene expression in treated patients and that peripheral blood mononuclear cells are suitable tissues for biomarker studies in future trials.