The farnesyl protein transferase inhibitor SCH66336 synergizes with taxanes in vitro and enhances their antitumor activity in vivo

Purpose: SCH66336 is an orally active, farnesyl protein transferase inhibitor. SCH66336 inhibits ras farnesylation in tumor cells and suppresses tumor growth in human xenograft and transgenic mouse cancer models in vivo. The taxanes, paclitaxel (Taxol) and docetaxel (Taxotere) block cell mitosis by enhancing polymerization of tubulin monomers into stabilized microtubule bundles, resulting in apoptosis. We hypothesized that anticancer combination therapy with SCH66336 and taxanes would be more efficacious than single drug therapy. Methods: We tested the efficacy of SCH66336 and taxanes when used in combination against tumor cell proliferation in vitro, against NCI-H460 human lung tumor xenografts in nude mice, and against mammary tumors in wap-ras transgenic mice. Results: SCH66336 synergized with paclitaxel in 10 out of 11 tumor cells lines originating from breast, colon, lung, ovary, prostate, and pancreas. SCH66336 also synergized with docetaxel in four out of five cell lines tested. In the NCI-H460 lung cancer xenograft model, oral SCH66336 (20 mg/kg twice daily for 14 days) and intraperitoneal paclitaxel (5 mg/kg once daily for 4 days) caused a tumor growth inhibition of 56% by day 7 and 65% by day 14 compared to paclitaxel alone. Male transgenic mice of the wap-ras/F substrain [FVB/N-TgN(WapHRAS)69LlnYSJL] spontaneously develop mammary tumors at 6–9 weeks of age which have been previously shown to be resistant to paclitaxel. Paclitaxel resistance was confirmed in the present study, while SCH66336 inhibited growth of these tumors. Most importantly, SCH66336 was able to sensitize wap-ras/F mammary tumors to paclitaxel chemotherapy. Conclusion: Clinical investigation of combination therapy using SCH66336 and taxanes in cancer patients is warranted. Further, SCH66336 may be useful for sensitizing paclitaxel-resistant tumors to taxane treatment. Received: 30 November 1999 / Accepted: 10 May 2000     

Internal mobility of PMMA in concentrated CDCl3 solutions, 2. 13C NMR spectra

The ¹³C NMR relaxation parameters (T₁, line widths and NOE factors) were measured and analyzed for two samples of atactic poly(methyl methacrylate) (PMMA) of molecular weight M_w 4,20·10⁴ and 1,76.10⁶ in CDCl₃ solutions in the concentration range 11 to 54% (by weight) of polymer, at 297 and 323 K. By this analysis it was found that the backbone segmental motion of PMMA is spatially isotropic in the whole measured concentration range; the motion of the α-CH₃ group may be approximated by the double reorientation model; the motion of the ester CH₃ group can be approximated by the isotropic model only at concentrations lower than 12%; in more concentrated solutions, a satisfactory approximation is obtained neither by the isotropic, nor by the double reorientation models. The reasons of this behaviour are discussed.     

The helmet sign: Physiologic radioactive accumulation after 131I therapy--a case report

After 131I radioablative treatment, a 51-y-old woman underwent whole-body (131)I scanning, which revealed intense uptake along the periphery of the skull. The patient disclosed that she had not washed her hair because she had obtained a new hairstyle between the 131I treatment and the scan. The intense uptake along the periphery of the skull represented radioactive physiologic accumulation at the patient's scalp.     

Radon-222 in drinking water of Karkonoskie Plateau

Radon-222 concentration in surface water, wells water and tap water in the main towns and villages which are located in area of Karkonoskie Plateau has been quantitative determined. The measurements were performed using the alpha liquid scintillation counting method. Majority of waterworks in Karkonoskie Plateau is supplied with the ground water in which the radon concentration is high from 87.5 Bq/l to 818.1 Bq/l. The waterworks in Karpacz are supplied with the surface water, which main characteristic is low radon concentration (below 10 Bq/l) and with the ground water have a high radon concentration (to 541 Bq/l). Radon-222 concentration in water of individual wells was similar to concentration in the ground water.     

An analytical model applied to a multicenter pneumococcal enzyme-linked immunosorbent assay study

Pneumococcal conjugate vaccines will eventually be licensed after favorable results from phase III efficacy trials. After licensure of a conjugate vaccine for invasive pneumococcal disease in infants, new conjugate vaccines will likely be licensed primarily on the basis of immunogenicity data rather than clinical efficacy. Analytical methods must therefore be developed, evaluated, and validated to compare immunogenicity results accurately within and between laboratories for different vaccines. At present no analytical technique is uniformly accepted and used in vaccine evaluation studies to determine the acceptable level of agreement between a laboratory result and the assigned value for a given serum sample. This multicenter study describes the magnitude of agreement among 12 laboratories quantifying an identical series of 48 pneumococcal serum specimens from 24 individuals (quality-control sera) by a consensus immunoglobulin G (IgG) enzyme-linked immunosorbent assay (ELISA) developed for this study. After provisional or trial antibody concentrations were assigned to the quality-control serum samples for this study, four methods for comparison of a series of laboratory-determined values with the assigned concentrations were evaluated. The percent error between assigned values and laboratory-determined concentrations proved to be the most informative of the four methods. We present guidelines that a laboratory may follow to analyze a series of quality-control sera to determine if it can reproduce the assigned antibody concentrations within an acceptable level of tolerance. While this study focused on a pneumococcal IgG ELISA, the methods that we describe are easily generalizable to other immunological assays.     

Heterotopic ossification in a lymph node with metastatic follicular carcinoma of thyroid: A case report

Metastasis of follicular thyroid carcinoma in a cervical lymph node associated with heterotopic ossification in a 34-year-old white female is presented. Pertinent gross and microscopic pathology is described and the literature is reviewed briefly. Bone formation in thyroid neoplasm has not been reported previously, except for bone metastases of medullary carcinoma.     

The North American Opiate Medication Initiative (NAOMI): Profile of Participants in North America’s First Trial of Heroin-Assisted Treatment

The North American Opiate Medication Initiative (NAOMI) is a randomized controlled trial evaluating the feasibility and effectiveness of heroin-assisted treatment (HAT) in the Canadian context. Our objective is to analyze the profile of the NAOMI participant cohort in the context of illicit opioid use in Canada and to evaluate its comparability with patient profiles of European HAT studies. Recruitment began in February 2005 and ended in March 2007. Inclusion criteria included opioid dependence, 5 or more years of opioid use, regular opioid injection, and at least two previous opiate addiction treatment attempts. Standardized assessment instruments such as the European Addiction Severity Index and the Maudsley Addiction Profile were employed. A total of 251 individuals were randomized from Vancouver, BC (192, 76.5%), and Montreal, Quebec (59, 23.5%); 38.5% were female, the mean age was 39.7 years (SD:8.6), and participants had injected drugs for 16.5 years (SD:9.9), on average. In the prior month, heroin was used a mean of 26.5 days (SD:7.4) and cocaine 16 days (SD;12.6). Vancouver had significantly more patients residing in unstable housing (88.5 vs. 22%; p < 0.001) and higher use of smoked crack cocaine (16.9 days vs. 2.3 days in the prior month; p < 0.001), while a significantly higher proportion of Montreal participants reported needle sharing in the prior 6 months (25% vs. 3.7%; p < 0.001). In many respects, the patient cohort was similar to the European trials; however, NAOMI had a higher proportion of female participants and participants residing in unstable housing. This study suggests that the NAOMI study successfully recruited participants with a profile indicated for HAT. It also raises concern about the high levels of crack cocaine use and social marginalization. Oviedo-Joekes, Marsh, Anis, and Schechter are with the School of Population and Public Health, University of British Columbia, Vancouver, BC, Canada; Oviedo-Joekes, Nosyk, Chettiar, Marsh, Krausz, Anis, and Schechter are with the Centre for Health Evaluation and Outcome Sciences, Providence Health Care, Vancouver, BC, Canada; Brissette and Schneeberger are with the Centre de recherche du l’Université de Montréal, Montreal, QC, Canada; Marsh and Krausz are with the Department of Psychiatry, University of British Columbia, Vancouver, BC, Canada; Marsh is with the Vancouver Coastal Health, Vancouver, BC, Canada; Marsh is with the Centre for Addiction Research British Columbia, Vancouver, BC, Canada.