Visualizing the kinetics of tumor-cell clearance in living animals.

Evaluation of potential antineoplastic therapies would be enhanced by noninvasive detection of tumor cells in living animals. Because light is transmitted through mammalian tissues, it was possible to use bioluminescence to monitor (both externally and quantitatively) growth and regression of labeled human cervical carcinoma (HeLa) cells engrafted into immunodeficient mice. The efficacy of both chemotherapy and immunotherapeutic treatment with ex vivo expanded human T cell-derived effector cells was evaluated. In the absence of therapy, animals showed progressive increases in signal intensity over time. Animals treated with cisplatin had marked reductions in tumor signal; 5'-fluorouracil was less effective, and cyclophosphamide was ineffective. Immunotherapy dramatically reduced signals at high effector-to-target cell ratios, and significant decreases were observed with lower ratios. This model system allowed sensitive, quantitative, real-time spatiotemporal analyses of the dynamics of neoplastic cell growth and facilitated rapid optimization of effective treatment regimens.

Noninvasive assessment of tumor cell proliferation in animal models.

Revealing the mechanisms of neoplastic disease and enhancing our ability to intervene in these processes requires an increased understanding of cellular and molecular changes as they occur in intact living animal models. We have begun to address these needs by developing a method of labeling tumor cells through constitutive expression of an optical reporter gene, and noninvasively monitoring cellular proliferation in vivo using a sensitive photon detection system. A stable line of HeLa cells that expressed a modified firefly luciferase gene was generated, and proliferation of these cells in irradiated severe combined immunodeficiency (SCID) mice was monitored. Tumor cells were introduced into animals via subcutaneous, intraperitoneal and intravenous inoculation and whole body images, that revealed tumor location and growth kinetics, were obtained. The number of photons that were emitted from the labeled tumor cells and transmitted through murine tissues was sufficient to detect 1x10(3) cells in the peritoneal cavity, 1x10(4) cells at subcutaneous sites and 1x10(6) circulating cells immediately following injection. The kinetics of cell proliferation, as measured by photon emission, was exponential in the peritoneal cavity and at subcutaneous sites. Intravenous inoculation resulted in detectable colonies of tumor cells in animals receiving more than 1x10(6) cells. Our demonstrated ability to detect small numbers of tumor cells in living animals noninvasively suggests that therapies designed to treat minimal disease states, as occur early in the disease course and after elimination of the tumor mass, may be monitored using this approach. Moreover, it may be possible to monitor micrometastases and evaluate the molecular steps in the metastatic process. Spatiotemporal analyses of neoplasia will improve the predictability of animal models of human disease as study groups can be followed over time, and this method will accelerate development of novel therapeutic strategies.

Correlates of serum lipids in a lean black population.

Exposure to an urban, sedentary work environment and higher socioeconomic status (SES) may stimulate adoption of Westernized lifestyles by populations in developing countries reversing the historically low risk for coronary heart disease. In a study of serum lipids in 1407 Nigerian civil servants, aged 25-54 years, we found a more atherogenic lipid profile among higher SES males and females compared with lower SES (LDL-cholesterol, 113 vs. 97 mg/dl, males, 125 vs. 114 mg/dl, females). Mean body mass index (BMI, kg/m2) in higher and lower SES was 22.6 and 21.3, respectively, males, and 24.7 and 24.4, respectively females. A strong relationship was observed between BMI and lipids although this relationship was absent among the leanest half of the population (BMI < 21.8). In multiple regression, SES and BMI were both strong and independent predictors of cholesterol. Both high and low SES consumed a typical Nigerian low fat, high carbohydrate diet, but somewhat higher meat, milk and egg intake suggested that some Westernization of the diet had occurred among the higher SES. Physical activity was lower among the higher SES. We conclude that SES related changes in lifestyle contribute to substantially higher total and LDL-cholesterol even in a generally lean population consuming a low fat diet.

Body fat distribution and other anthropometric blood pressure correlates in a Nigerian urban elderly population.

Blood pressure (BP) has been reported to be more consistently correlated with body mass index (BMI) than with waist-hip ratio (WHR) in Blacks. We present the correlates of BP in a systematic sample of 152 (65.7 pc response rate) elderly urban Nigerians, with a mean age of 72.7 yrs. +/- 12.1 for males and 73.2 yrs, +/- 11.9 for females. There were 12.3 pc and 22.3 pc obesity rates in the males and females respectively, with an equivalent mean BMI of 22.8 kg/m2 and 23.4 kg/m2 and WHR of 0.97 and 0.94. Systolic blood pressure (SBP) and diastolic blood pressure (DBP) correlated with BMI, r = 0.26; p < 0.01 and r = 0.42; p < 0.001, only in females. WHR did not correlate with BP in either sex, but waist and hip measurements correlated significantly with BP in both sexes. The most important predictor of BP is BMI for females and waist measurement for men. Although smoking and alcohol were not related to BP in either sex, the data suggests that alcohol enhanced, while tobacco inhibited weight gain significantly in males, who on the whole indulged more than the females. Fasting or two hour whole blood glucose were not related to BP. The findings are in support of the adverse effects of weight on BP in the elderly. There is need to study attitudes to adult weight gain as expressed in body shape, and to use the findings in the development of weight control programmes as part of blood pressure control in the elderly.

High incidence of poor sulfoxidation in patients with primary biliary cirrhosis.

An impaired sulfoxidation pathway has been implicated in the pathogenesis of chlorpromazine-induced hepatotoxicity. Since some patients with chronic chlorpromazine-induced cholestasis may have features of primary biliary cirrhosis, we studied the ability to sulfoxidate the amino acid analogue S-carboxymethyl-cysteine in 44 patients with primary biliary cirrhosis and in two control groups--one without liver disease and one with a variety of liver diseases other than primary biliary cirrhosis. Poor sulfoxidation was observed in 84 percent of the patients with primary biliary cirrhosis, as compared with 24 percent of patients with other liver diseases and 22 percent of normal controls (P less than 0.0005 for both comparisons). Poor sulfoxidation did not correlate with the degree of hyperbilirubinemia or histologic severity of liver disease in any of the groups studied. There was an inverse correlation with age only in the patients with primary biliary cirrhosis (r = -0.44, P less than 0.001). Liver transplantation was performed in six of the patients and improved sulfoxidation in five; in the four with primary biliary cirrhosis, sulfoxidation improved from poor to good or intermediate. We conclude that poor sulfoxidation is closely associated with primary biliary cirrhosis but not with the other liver diseases we studied.