New potent verapamil derivatives that reverse multidrug resistance in human renal carcinoma cells and in transgenic mice expressing the human MDR1 gene.

Multidrug resistance in human renal cell carcinoma is mainly caused by expression of the MDR1 gene and is characterized by a broad spectrum cross resistance to many natural product chemotherapeutic agents. This resistance can be overcome by applying chemosensitizers which inhibit the function of the MDR1 gene product P-glycoprotein. The development of new reversing agents with fewer side effects and a higher potency in modifying resistance is a high priority of research on drug resistance. We have evaluated four new verapamil derivatives on 21 primary human renal cell carcinomas in vitro, and also tested them in an MDR-transgenic mice model. These mice express the human MDR1 gene in their bone marrow cells and measurement of their white blood counts provides a simple, rapid and reliable system to screen for the potency of MDR-reversing agents in vivo. We demonstrate here that all four drugs are effective in reversing multidrug resistance in primary cultures of human renal cell carcinomas when used in combination with vinblastine chemotherapy, and to a lesser extent with doxorubicin or daunomycin chemotherapy. Our in vivo data indicate that two of these reversing agents display low toxicity at high concentrations and are more effective at low, clinically achievable concentrations, than the other two drugs and R-verapamil. These results make the two new drugs attractive candidates to be taken into clinical trials.     

Body fat in identical twins reared apart: Roles for genes and environment

We report analyses of data on body fat from a cohort of 34 separated monozygotic twin pairs (MZA) and a matched sample of 38 pairs of monozygotic twins reared together (MZT) originally studied by James Shields. The correlation for MZA pairs was. 61 and the correlation for MZT pairs was. 75. These correlations did not differ significantly, nor did correlations differ between MZA pairs subclassified as having been raised in relatively more or less similar environments. Our results suggest important roles for both genes and environment in the accumulation of body fat and support other adoption studies in suggesting that adult environments rather than rearing environments are the most important nongenetic determinants of levels of body fat in adults.Supported by National Institute of Mental Health Grant MH43409 to R.A.P. and a Grant in Aid from the Dight Institute of Human Genetics to I.I.G.     

Familial hyperparathyroidism in association with colonic carcinoma

A unique case of familial hyperparathyroidism associated with carcinoma of the colon is presented. Two brothers presented initially with colonic carcinoma and years later both were found to have primary hyperparathyroidism on the basis of parathyroid hyperplasia. This raises the issue of associated malignancies in patients with hyperparathyroidism, especially if they are found to be familial. One member of the family developed severe, recurrent hypercalcemia with bone disease, and thus the need for continued follow-up is emphasized.     

Localization of a gene for otosclerosis to chromosome 15q25-q26

Among white adults otosclerosis is the single most common cause of hearing impairment. Although the genetics of this disease are controversial, the majority of studies indicate autosomal dominant inheritance with reduced penetrance. We studied a large multi- generational family in which otosclerosis has been inherited in an autosomal dominant pattern. Five of16 affected persons have surgically confirmed otosclerosis; the remaining nine have a conductive hearing loss but have not undergone corrective surgery. To locate the disease- causing gene we completed genetic linkage analysis using short tandem repeat polymorphisms (STRPs) distributed over the entire genome. Multipoint linkage analysis showed that only one genomic region, on chromosome 15q, generated a lod score >2.0. Additional STRPs were typed in this area, resulting in a lod score of 3.4. STRPs FES (centromeric) and D15S657 (telomeric) flank the 14. 5 cM region that contains an otosclerosis gene.