Clin Cancer Res
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Approximately 30% of ovarian and breast cancers overexpress p185(c-erbB-2) with as many as 10(6) receptors/cell. Normal cells have as few as 10(4) receptors/cell. We have examined the susceptibility of SKOv3 human ovarian cancer cells to anti-c-erbB2 antibodies and immunotoxins as a function of c-erbB-2 density on the cell surface. ⋯ Importantly, tumor cells that had survived first treatment with anti-p185(c-erbB2)-RTA alone still retained sensitivity to repeat treatment with the same immunotoxin and also proved susceptible to the synergistic cytotoxicity of anti-p185(cerbB-2)-RTA in combination with anti-p170(EGFR)-RTA. Growth characteristics of the clones expressing various levels of p185(c-erbB-2) were also studied. No correlation was found between p185(c-erbB-2) expression levels and the rate of anchorage-dependent growth, anchorage-independent growth, or in vivo growth in nude mice.
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Isolated organ perfusion of the liver or extremity with tumor necrosis factor (TNF) and melphalan results in regression of bulky tumors in the majority of patients. The efficacy of TNF in this setting is not known, although data suggest that it may exert antitumor effects primarily on tumor-associated neovasculature. We studied the effects of TNF on capillary leak in liver and tumor tissue during isolated hepatic perfusion (IHP) with melphalan. ⋯ Capillary leak, as reflected by diffusion of I-131 radiolabeled albumin into the interstitial space, is comparable in liver and tumor before IHP but is significantly higher in tumor after IHP. The increased diffusion in the capillary tumor bed must occur through TNF-independent mechanisms such as intrinsic features of tumor neovasculature, hyperthermia, or other unrecognized perfusion-related factors. These data indicate that TNF must continue to be critically evaluated in clinical trials before it is routinely used with melphalan in isolated organ perfusion.
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Recent experiments in mice have demonstrated that the systemic exposure to p.o. administered paclitaxel is significantly enhanced with coadministration of the P-glycoprotein blocker SDZ PSC 833 (J. van Asperen et al, Br. J. Cancer, 76: 1181-1183, 1997). ⋯ A histological examination revealed that the enhanced absorption was not caused by gastrointestinal toxicity. We conclude that cyclosporin A and SDZ PSC 833 are equally effective in increasing the systemic exposure to p.o. administered paclitaxel. These data are promising for the development of a clinically useful oral formulation of this cytostatic drug and indicate that cyclosporin A is a suitable agent for further research of this concept.
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Randomized Controlled Trial Clinical Trial
Phase I trial of cremophor EL with bolus doxorubicin.
Cremophor EL (cremophor), a component of the paclitaxel formulation, can potentially reverse P-glycoprotein-associated multidrug resistance. A Phase I trial of cremophor as a 6-h infusion every 3 weeks was performed with bolus doxorubicin (50 mg/m2). The cremophor dose was escalated from 1 to 60 ml/m2. ⋯ One patient with hepatoma resistant to epirubicin achieved a near-complete response. Cremophor 45 ml/m2 over 6 h with 35 mg/m2 doxorubicin is recommended for further studies. The pharmacokinetic interaction between cremophor and doxorubicin is quantitatively similar to that described in trials of paclitaxel with doxorubicin and suggests that the cremophor in the paclitaxel formulation is responsible.
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Our objective was to determine the effect of neoadjuvant hormonal therapy on the presence of circulating prostate cells in patients undergoing radical prostatectomy for prostate cancer. A total of 60 patients at high risk for extraprostatic disease were analyzed for the presence of circulating prostate cells using reverse transcriptase PCR (RTPCR) amplification of the prostate-specific antigen mRNA. Twenty-nine patients underwent radical prostatectomy for a clinical T2b-c tumor or a stage T1c-T2a tumor and a serum prostate-specific antigen level > or =10ng/ml (radical prostatectomy alone), and 31 similarly staged patients received neoadjuvant hormonal therapy before radical prostatectomy (neoadjuvant). ⋯ These data suggest that a subset of the neoadjuvant patients are converted to organ confined disease without eliminating the prostate cells in the bone marrow. Our data suggest that hormonal therapy before radical prostatectomy decreases the occurrence of extraprostatic disease but, to a lesser degree, the incidence of circulating prostate cells. This may partially explain why hormonal therapy before radical prostatectomy has not improved disease-free survival.