Effect of cocaine metabolites on behavior: possible neuroendocrine mechanisms.

The predominant cocaine metabolites were tested for central nervous system effects by intracerebroventricular (ICV) administration in rats. We found two types of responses: cocaine, norcocaine (NC), benzoylecgonine (BE), and benzoylnorecgonine (Nor BE) produced stimulatory effects, whereas ecgonine methyl ester (EME) and ecgonine (EC) resulted in no specific effect or sedation. A novel metabolite interaction was revealed when rats were pretreated with EME, which inhibited both analgesia and seizures by subsequently administered cocaine. Pretreatment with EC inhibited both cocaine and BE seizures and seizure-associated death. Direct injection of EME into the nucleus accumbens significantly suppressed systemic cocaine potentiation of intracranial electrical self-stimulation of the ventral tegmental area, whereas corticotropin releasing hormone injected ICV selectively potentiated BE-induced seizures and death. These results confirm multiple, metabolite-mediated activities in the central nervous system. Pharmacological interactions of the metabolites with each other and/or with neurohormones may help explain some of the pathophysiological effects seen in human chronic cocaine abuse.

Cocaine analgesia: an in vivo structure-activity study.

Hot plate testing of rats was performed to determine the optimal analgesic doses of intracerebroventricularly (ICV) administered cocaine, significant cocaine metabolites, and selected structurally similar molecules. Optimal, (subseizure) analgesic doses for cocaine and selected cocaine analogues were (in microM): cocaine, 0.37; cocaethylene, 0.09; benzoylecgonine, 0.35; norcocaine, 0.43; and ecgonine, 2.1. Ecgonine methyl ester was not analgesic at < or = 3.7 microM. These results, in conjunction with findings on other structurally similar molecules suggest that, of the molecules tested, (a) a hydrophobic group at the C-3 attached carbon is critical for analgesia; (b) a hydrophobic C-2 ester group can enhance analgesic activity (e.g., cocaethylene); (c) the N-methyl position is minimally important for analgesia; and (d) isomeric configurational changes can influence analgesia.

Segregation analysis of hereditary nonpolyposis colorectal cancer.

Segregation analysis of eleven families comprising 2762 individuals indicated compatibility of the data with segregation of a major autosomal dominant gene for hereditary nonpolyposis colorectal cancer. It was estimated that between 71% and 79% of the gene carriers were susceptible and had age of onset that was normally distributed with mean about 47 and standard deviation about 10 years. There was a low frequency of sporadic cases at the older ages, a little less than four percent of nongene carriers being affected by age 80. No significant differences were found between the families exhibiting endometrial cancer (cancer family syndrome) and those not exhibiting endometrial cancer (hereditary site-specific nonpolyposis colonic cancer).

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). I. Clinical description of resource.

Hereditary nonpolyposis colorectal cancer (HNPCC) is comprised of the following: the cancer family syndrome (CFS), or Lynch syndrome II, which shows early-onset proximal colonic cancer predominance and other associated extracolonic adenocarcinomas, particularly endometrial carcinoma; and hereditary site-specific colon cancer (HSSCC), or Lynch syndrome I, which shows all of the same characteristics, except for extracolonic cancer. Nine families with CFS and two with HSSCC provided the resource that was tested for biomarkers (see companion article). All families were meticulously evaluated for genealogy and cancer verification. Biologic specimens were obtained during field visits to areas of closest geographic proximity to the families. Cancer education and recommendations for surveillance/management were provided to patients and their physicians. Additionally, 40 families (about 3000 individuals) with either CFS or HSSCC have been ascertained. Syndrome cancers were restricted to direct-line relatives as opposed to nonbloodline relatives, arguing against involvement of environmental factors. One documented clinical feature was a predilection for proximal versus distal colonic cancer in both CFS and HSSCC kindreds. This has important clinical significance in that it clarifies the need for instituting effective surveillance earlier to detect the predominantly proximal colonic cancers.

Hereditary nonpolyposis colorectal cancer (Lynch syndromes I and II). II. Biomarker studies.

Nine families with the cancer family syndrome (CFS), or Lynch syndrome II, and two with hereditary site-specific colonic cancer (HSSCC), or Lynch syndrome I, were investigated for the following potential biomarkers of genotype status: in vitro tetraploidy of dermal fibroblast monolayer cultures; tritiated thymidine uptake (3HdThd) labeling of colonic mucosa; cytogenetics of peripheral blood mononuclear leukocytes; quantitative serum immunoglobulin determinations; methionine dependence in dermal fibroblasts in tissue culture; segregation analysis; and the study of gene linkage with respect to 25 landmark serum and blood group markers. Positive lod scores of 3.19 for linkage of the Jk (Kidd blood group) with CFS were obtained. Both in vitro tetraploidy and 3HdThd uptake in the distal colonic mucosal crypt compartments were positively associated with cancer risk status in CFS and HSSCC kindreds. There was a high incidence of polymorphisms of centromeric heterochromatin, including complete inversion. These findings are of particular clinical and genetic significance because HNPCC lacks premonitory signs of cancer risk. If confirmed, they could conceivably enable definition of genotype as early as birth in members of HNPCC kindreds, thereby enabling psychologic preparation and intensive cancer education for improved compliance in surveillance/management programs. These studies also provide new clues about the chromosome(s) bearing the presumed cancer gene(s). For example, CFS gene(s) may possibly be located on chromosome 2, where Jk is located. These biomarkers merit intensive study in additional HNPCC kindreds for a more complete assessment of their sensitivity and specificity. Additionally, essential aspects of previous reports involving biologic samples from these and/or similar subject kindreds are included to permit a comprehensive presentation of the combined findings of this consortium to date.

Hereditary nonpolyposis colorectal cancer in a Navajo Indian family.

The purpose of this report is to describe a unique Navajo Indian kindred that manifests a tumor pattern consonant with hereditary nonpolyposis colorectal cancer (HNPCC). So far as we can determine this is the first report of HNPCC among American Indians.

Hereditary ovarian carcinoma. Biomarker studies.

Three ovarian-cancer-prone kindreds were studied, two of which contained identical twin sisters concordant for ovarian carcinoma. In one kindred, both identical twin sisters had daughters with ovarian carcinoma. In another kindred, one of the identical twin sisters had an ovarian-cancer-affected daughter. Ovarian carcinoma showed vertical transmission in all three families in a pattern consonant with an autosomal dominant mode of inheritance. Medical-genetic survey of each family included detailed questionnaires with retrieval of primary medical and pathology documents on cancer of all anatomic sites. Putative biomarker determinations included: (1) in vitro hyperdiploidy in dermal monolayer cultures; and (2) lower serum levels of alpha-L-fucosidase (less than or equal to 275 IU/ml) in all cancer-affected patients and statistically significant lower levels in 50% risk individuals when compared to spouse and published controls (P = 0.04 and P = 0.0002, respectively). These findings are discussed in context with the eventual development of a risk factor profile which, given acceptable sensitivity and specificity, would enable identification of individuals who would be prime candidates for intensive surveillance/management programs.

Biomarker studies in hereditary ovarian carcinoma.

Ovarian cancer has been increasing in frequency during the past several decades, particularly in Western industrialized nations. It has the ignominious distinction of being the major cause of death from genitourinary cancer in women in the United States. A small but significant fraction of patients with ovarian cancer have family histories that are compatible with a primary genetic factor. The hereditary variant is heterogeneous but these pedigrees reveal a high predictability of cancer. Therefore, families that are prone to ovarian cancer merit the highest priority for biomarker investigations. When considering the generally poor surveillance measures available to us for detecting ovarian cancer sufficiently early to improve prognosis, the search for biomarkers of high sensitivity and specificity assumes major significance. In turn, such biomarkers may shed light on the etiology and pathogenesis of ovarian cancer in the general population and more importantly provide mechanisms for early detection and prevention of death from this tumor.

Is cancer communicable?

Recent developments in cancer epidemiology have led to the possibility of an exceedingly complex communicable factor(s) in cancer etiology. The transmission of such an agent(s) may require a susceptible genotype and/or other promotional events. Likely candidates which support this supposition include: Epstein-Barr virus (nasopharyngeal carcinoma, Burkitt's lymphoma, salivary gland tumor among Eskimos, X-linked lymphoproliferative syndrome of Purtilo); human T-cell leukemia virus (adult T-cell leukemia); acquired immune deficiency syndrome (AIDS), complicated by Kaposi's sarcoma (etiologic agent remains elusive, though epidemiology suggests possible infectious transmission); abnormal immune phenomena in households of Hodgkin's disease patients; and clustering of various types of cancer in spouses, the general population, and families. We have selectively reviewed the literature and evolved an etiologic hypothesis which integrates a communicable agent(s) in concert with genetic and/or environmental carcinogenic interaction which could conceivably explain a significant fraction of the total cancer burden.

Genetics of rectal cancer.

Two operational subdivisions of hereditary colorectal cancer susceptibility are those with and those without premalignant adenomatous colonic polyp expression. In both of these subdivisions, reliable biomarkers of gene carriage would be of value in patient management as we have previously emphasized. Consideration must also be given to the familial (hereditary) occurrence of inflammatory bowel diseases associating with colorectal cancer susceptibility. The occurrence of rectal cancers should therefore alert the physician to investigate the possibility of a significant family medical history in order to fully elucidate the genetic heterogeneity of susceptibility to this disease. Clinicians should also be alert to the possibility of extracolonic malignancies where probable genetic colorectal cancer susceptibility is evident. Whenever possible, all potential biomarkers should be investigated to aid in definition of genetic heterogeneity.

Effects of common analgesics on the in vitro suppression of lymphocyte mitogen responses by cephalosporins.

Acetaminophen and indomethacin either did not alter or partially reversed the inhibition of lymphocyte mitogenic responses by cephalosporins. Aspirin at concentrations of >/=100 mug/ml in cultures containing cephalosporins reduced the response below the level with either drug alone.