Cancer research
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We report the genetic construction and expression of a fusion protein between an antibody single chain-linked variable domain fragment specific for human carcinomas and beta-lactamase II from Bacillus cereus. Sequences encoding the variable regions of the L6 monoclonal antibody were assembled so as to be separated from each other by an 18-amino acid linker and from the mature form of beta-lactamase by a 6-amino acid linker. The construct was placed under the transcriptional regulation of the lac promoter, and the PelB signal sequence was used to direct export of the fusion protein to the periplasmic space of Escherichia coli. ⋯ The fusion protein was shown to bind to tumor cells at least as well as chemically prepared F(ab') and to maintain beta-lactamase activity at a level similar to that of the native enzyme. Tumor cells coated with the fusion protein were sensitive to a cephalosporin mustard prodrug in a dose-dependent fashion comparable to that of enzyme chemically conjugated to F(ab'). This article demonstrates the feasibility of using single chain-linked variable domain-enzyme fusion proteins for the activation of anticancer prodrugs.
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A population-based screening for detection of early cancers evaluated the prevalence of precancerous gastric lesions in an area in Shandong province, China, with one of the world's highest rates of stomach cancer. A total of 3433 residents aged 35 to 64 yr received gastroscopical examinations with biopsies taken from standard locations. Chronic atrophic gastritis was nearly universal; less than 2% of the population had biopsies showing entirely normal mucosa or only superficial gastritis. ⋯ Intestinal metaplasia and gastric dysplasia were detected throughout the stomach, but the lesions were more pronounced along the lesser curvature, especially in the angulus and antrum. There was no sex difference in rates of chronic atrophic gastritis, but males had a slightly higher prevalence of intestinal metaplasia, a 1.6-fold increase in dysplasia, and a 3-fold excess of gastric cancer. The data quantify the extensiveness of gastric lesions likely to be involved in the natural history of stomach cancer in this high-risk population.
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We investigated the serum concentrations of a variety of cytokines [granulocyte-macrophage-colony-stimulating factor (GM-CSF), granulocyte colony stimulating factor (G-CSF), interleukin (IL) 1 alpha, IL-3, IL-6, IL-8, erythropoietin, tumor necrosis factor alpha, gamma-interferon in 10 patients with advanced ovarian cancer undergoing autologous peripheral blood stem cell (PBSC) harvesting followed by treatment with high-dose cisplatin, etoposide, and carboplatin and PBSC transplantation (chemotherapy was administered on days 1 through 3, PBSCT on day 6). Preliminary observations on cytokine serum levels were performed for 4 patients; on this basis, the kinetics of cytokines was then investigated in greater detail at closely sequential times in 6 further patients. We observed a consistent pattern of sequential GM-CSF, G-CSF, and IL-8 release after chemotherapy/PBSCT in all 10 cases, including the 6 patients monitored in detail: (a) at days 5-10 a GM-CSF peak; (b) at days 12-14 a pronounced release of both G-CSF and IL-8, which always preceded granulocyte recovery by approximately 7 days. ⋯ An early peak of IL-1 alpha was observed in all 3 analyzed patients, while an IL-6 peak was monitored at days 13-15 in all 4 patients analyzed in detail. The present results indicate a sequential coordinate pattern of cytokine release after ablative therapy and PBSCT and shed light on the mechanisms mediating the recovery of granulocytes, and more generally of hematopoiesis, after stem cell transplantation. Furthermore, these studies may contribute to the design of improved protocols for cytokine administration following myelosuppressive anticancer therapy, as well as to the prediction of granulocytic response.
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Clinical Trial
Pediatric phase I trial and pharmacokinetic study of topotecan administered as a 24-hour continuous infusion.
Topotecan, a water-soluble semisynthetic analogue of camptothecin, is the first topoisomerase I inhibitor to undergo evaluation in pediatric patients with refractory malignancies. A phase I and pharmacokinetic study was performed to determine the maximum tolerated dose (MTD) and dose-limiting toxicities, the incidence and severity of other toxicities, and the pharmacokinetics of topotecan in children. Twenty-nine patients received 42 courses of i.v. topotecan administered as a 24-h continuous infusion every 21 days at doses ranging from 2.0 to 7.5 mg/m2. ⋯ The recommended starting dose for phase II pediatric trials is 5.5 mg/m2. Although this dose exceeds the MTD identified in heavily pretreated adult patients receiving topotecan on the same schedule, it is less than the MTD for minimally pretreated adult patients. Therefore, dose escalation to 7.5 mg/m2 in phase II pediatric trials should be considered for patients who tolerate treatment well at the 5.5-mg/m2 dose.
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Clinical Trial
Phase I and pharmacokinetic study of Taxotere (RP 56976; NSC 628503) given as a short intravenous infusion.
Taxotere (N-debenzoyl-N-tert-butoxycarbonyl-10-deacetyl Taxol; RP 56976; NSC 628503) is a semisynthetic analogue of Taxol. It is twice as active in inhibiting tubuline depolymerization and has a better in vivo activity on B16 melanoma, with responses in advanced colon 38 and PO3 adenocarcinoma. Sixty-five patients (49 women, 16 men), with a median age of 57 years, received 248 courses of Taxotere given as a 1-2-h i.v. infusion every 2 or 3 weeks. ⋯ AUC correlated with the percentage decrease of neutrophils in a sigmoid Emax model. The renal excretion of unchanged Taxotere was very low (< 5% of the dose). The recommended dose for phase II trials with this schedule is 100 mg/m2 every 3 weeks.