Biomedical subjects

E O George

Publications and source records attributed to E O George.

8 recordsLinked to original sources

PubMed1999

Synergy of topotecan in combination with vincristine for treatment of pediatric solid tumor xenografts.

Topotecan and vincristine were evaluated alone or in combination against 13 independent xenografts and 1 vincristine-resistant derivative, representing childhood neuroblastoma (n = 6), rhabdomyosarcoma (n = 5), or brain tumors (n = 3). Topotecan was given by i.v. bolus on a schedule found previously to be optimal. Drug was administered daily for 5 days on 2 consecutive weeks with cycles repeated every 21 days over a period of 8 weeks. Doses of topotecan ranged from 0.16 to 1.5 mg/kg to simulate clinically achievable topotecan lactone plasma systemic exposures. Vincristine was administered i.v. every 7 days at a fixed dose of 1 mg/kg. Given as a single agent, vincristine induced complete responses (CRs) in all mice bearing two rhabdomyosarcomas (Rh28 and Rh30) and some CRs in Rh12-bearing mice (57%) but relatively few CRs (<29%) in other tumors. As a single agent, topotecan induced CR in a low proportion of tumor lines. A dose-response model with a logit link function was used to investigate whether the combination of topotecan and vincristine resulted in greater than expected responses compared with the activity of the agents when administered alone. Only CR was used to evaluate tumor responses. The combination resulted in significantly greater than expected CRs than individual agents in nine tumor lines (four neuroblastoma, three brain tumors, and two rhabdomyosarcomas). Similar event-free (failure) distributions were shown in SJ-GBM2 glioblastoma xenografts, whether vincristine was administered on day 1 or day 5 of each topotecan course. To determine whether the increased antitumor activity with the combination was attributable to a change in drug disposition, extensive pharmacokinetic studies were performed. However, little or no interaction between these two agents was determined. Toxicity of the combination was marked by prolonged thrombocytopenia and decreased hemoglobin. However, approximately 75 and 80% of the maximum tolerated dose of each single agent, topotecan (1.5 mg/kg) or vincristine (1 mg/kg), could be given in combination, resulting in a combination toxicity index of approximately 1.5. These results show that the therapeutic effect of combining topotecan with vincristine was greater than additive in most tumor models of childhood solid tumors, and toxicity data suggest that this can be administered to mice with only moderate reduction in the dose levels for each agent.

Animals↗

PubMed1998

Bax is an important determinant of chemosensitivity in pediatric tumor cell lines independent of Bcl-2 expression and p53 status.

Susceptibility of a tumor cell to undergo chemotherapy-induced apoptosis appears to be dependent upon the balance of proapoptotic and survival factors that are expressed within any given cell. We have chosen to evaluate how expression of several of these proteins influences chemosensitivity of a panel of 10 pediatric tumor cell lines chosen from three tumor histiotypes: neuroblastoma, rhabdomyosarcoma, and pediatric glial tumors. The proteins evaluated were p53 and six members of the Bax/Bcl-2 family: three proapoptotic proteins (Bax, Bak, and Bcl-xS) and three survival factors (Bcl-2, Bcl-xL, and Mcl-1). We investigated whether there was any relationship between endogenous expression of these proteins and chemosensitivity (or resistance) to three chemotherapeutic agents that directly damage DNA (doxorubicin, actinomycin D, and topotecan) and a mitotic spindle poison (vincristine). Even though exogenous overexpression of wild-type p53 has been associated with a chemosensitive phenotype in several model systems we demonstrated no such relationship in these studies. In addition, expression levels of Bcl-2, Bcl-xL, Bcl-xS, Bak, or Mcl-1 did not correlate with sensitivity or resistance to the four drugs. However, there was a statistically significant correlation between endogenous levels of Bax protein and sensitivity to both doxorubicin and actinomycin D. We conclude that even though many proteins such as p53 and Bcl-2 have been shown to influence drug response when exogenously overexpressed in model systems, in unmodified cell lines endogenous protein levels may not generate the same results. We have demonstrated that endogenous Bax expression was the only protein found to be associated with chemosensitivity across the three different tumor histiotypes and propose that analysis of Bax may be a more useful prognostic indicator for tumor response to therapy than either p53 or Bcl-2.

Animals↗

PubMed1997

Testing for treatment related trend with partially exchangeable clustered data.

When testing for treatment related effect, it is common to focus on data that describe some primary response, even though an experiment might yield data on secondary, less conspicuous effects. An example of such an experiment can be found in developmental toxicity studies, where a primary response might be the presence of skeletal malformation in a fetus, and a secondary effect might be reduced weight. In such studies, weight reduction may occur not only among malformed fetuses, but also among normal fetuses. In this paper, we use a likelihood ratio procedure to construct treatment related trend tests for developmental experiments with such outcomes. We assume that within each cluster, data are partially exchangeable and we use the presence or absence of malformations as categorical covariates. Two models are considered for the covariance structures: In the general model, partially exchangeable covariance matrices are used for each cluster within dose groups. In the homogeneous model, a common exchangeable covariance matrix is used for all clusters. Maximum likelihood estimates (MLEs) of unknown parameters in the general model are obtained by directly maximizing the log-likelihood function through careful numerical consideration, while MLEs of parameters of teh homogeneous model are obtained through an iterative procedure. Two applications to developmental toxicity data are described.

Abnormalities, Drug-Induced↗

PubMed1997

Nutrition assessment in children with sickle cell disease.

Children with sickle cell disease have decreased height and weight when compared with their peers. Although exact reasons for poor growth have not been established, increased calorie and protein needs and deficiencies in zinc, folic acid, and vitamins A, C, and E may be factors. To determine whether inadequate nutrient intake contributes to this poor growth, we conducted a survey of the nutrition knowledge and practices of families affected by sickle cell disease. Sixty-one patients with a median age of 8 years (range, 13 months to 17 years) participated in the study. Patients with homozygous S hemoglobin (sickle cell) disease (Hb SS, n = 34) and sickle beta zero thalassemia (Hb S beta zero-thalassemia, n = 2) were combined; 19% were below the fifth percentile for height. The other patients, with sickle hemoglobin C disease (Hb SC, n = 21) and sickle beta plus thalassemia (Hb beta(+)-thalassemia, n = 4), were grouped, and 4% were below the fifth percentile for height (P = .043). Ninety percent of the study patients or their parents were familiar with the food groups indicated on the US Department of Agriculture's Food Guide Pyramid, but most patients failed to consume appropriate amounts from those groups. Although two thirds of the patients ate the recommended number of servings daily from the meat group, only 20% to 31% of the recommended servings from each of the other food groups was consumed. This was possibly related to low socioeconomic status. The patients in the Hb SS group ate significantly less from the bread (P < .037) and milk (P < .022) categories than the patients in the Hb SC group. Fifty-nine percent of families had incomes below the poverty level, and 79% participated in a food assistance program. We conclude that the nutrient intake of patients with sickle cell disease is often inadequate. Education for patients with sickle cell disease should focus on (1) specific nutrient needs, with proper distribution of dietary intake among the food groups, (2) ways to provide nutritious meals on a limited income, and (3) methods for increasing calorie and protein intake.

Adolescent↗

PubMed1995

A full likelihood procedure for analysing exchangeable binary data.

A full-likelihood procedure is proposed for analyzing correlated binary data under the assumption of exchangeability. The binomial and beta-binomial models are shown to occur as special cases correspondingly, respectively, to the choice of degenerate and beta-mixing distributions. For a finite exchangeable binary sequence of random variables, expressions for the joint distribution, moments, and correlations of all orders are derived. Maximum likelihood estimates of the moments of all orders are computed and used to estimate correlations and the distribution of the number of responses in a cluster. In an application to developmental toxicology data analysis, the procedure introduced is compared with a beta-binomial and a generalized estimating equation procedure in which mean response and intralitter correlation are linked to dose.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed1995

Estimating variance functions in developmental toxicity studies.

The presence of intralitter correlation is a well known issue for analysis of the developmental toxicology data. The intralitter correlation coefficients observed in developmental toxicology data are generally different across dose groups. In this paper we use a generalized estimating equation procedure to model jointly the mean parameters and the intralitter correlation coefficients as functions of dose levels. Our procedure is similar to that used by Prentice and Zhao (1991, Biometrics 47, 825-839) for estimating the mean and variance parameters.

2,4,5-Trichlorophenoxyacetic Acid↗

PubMed1993

Generalized logistic models for low-dose response data.

We discuss a generalization of the logistic response function of the form Pr(y = 1/x) = [1 + exp(- theta - beta'x)]-alpha, where alpha > 0. This function coincides with the usual logistic response when the shape parameter alpha is equal to one. We describe the use of this model for analysing cancer rates in mice for low-dose exposure to a known carcinogen. When estimating the low-dose responses, the errors associated with extrapolation are reduced when a priori knowledge about the rates among unexposed individuals is incorporated into the fitting procedures.

2-Acetylaminofluorene↗

PubMed1993

The effect of time after treatment, treatment schedule and animal age on the frequency of 6-thioguanine-resistant T-lymphocytes induced in Fischer 344 rats by N-ethyl-N-nitrosourea.

The persistence of 6-thioguanine-resistant (TGr) T-lymphocytes was investigated in Fischer 344 rats treated with N-ethyl-N-nitrosourea (ENU) using two schedules. Male rats, aged 3 months, were given i.p. injections containing a total of 0, 50 or 100 mg ENU/kg either as a single treatment (single-dose group) or divided among 10 weekly treatments (split-dose group). At 1, 3, 5, 10, 20, 30 and 50 weeks after the single-dose treatment, and 10, 20, 30 and 50 weeks after beginning the split-dose regimen, animals were assayed for the frequency of TGr spleen lymphocytes. ENU produced significant dose- and time-dependent responses in the single- and the split-dose treatment groups. Although a few of the 50 mg/kg split-dose treatments were significantly higher than the comparative single-dose groups, the number of TGr lymphocytes produced by the two dosing regimens were generally similar. The frequency of TGr cells for control animals increased with the age of the animals. The mode of ENU administration did not greatly influence the percent cloning efficiency (%CE) of the non-selection cultures, although the %CE declined in animals over 10 months of age. To investigate the relationship between the frequency of TGr cells and the age of the animals at the time of ENU administration, additional rats aged 17 months were treated with a single dose of ENU and at 1, 5 and 10 weeks following exposure, the frequencies of TGr cells were determined from the isolated lymphocytes. No difference in mutagen sensitivity between rats treated at 3 months of age and those treated at 17 months of age was detected at the time points evaluated. The data demonstrate the persistence of ENU-induced TGr T-lymphocytes in the rat and suggest that the dose and possibly the treatment schedule, but not the age of the animal at the time of treatment, affect the response.

Age Factors↗