INACTIVATION OF MUTAGENIC DRUGS AND THEIR METABOLITES IN THE URINE OF PATIENTS ADMINISTERED ANTINEOPLASTIC THERAPY

Urines from patients administered mutagenic antineoplastic drugs were significantly mutagenic in the Ames assay, and hence may pose a genotoxic hazard to hospital personnel or family members caring for the patient. The urines were tested for mutagenicity in several different strains of Salmonella typhimurium that were uvr positive or negative (TA98, TA100, TA102, UTH8413, UTH8414). The urines were fractionated by high pressure liquid chromatography (HPLC) and the fractions assayed for mutagenicity in the strains in which the whole urine was mutagenic. Only fractions of urines containing the parent compound (cisplatin, doxorubicin, or mitomycin) were mutagenic; no other fraction showed significant mutagenicity. However, urine containing cyclophosphamide had two fractions that were mutagenic. One fraction, the fraction containing cyclophosphamide, required metabolic activation for mutagenicity. The other fraction did not require activation for mutagenicity.^ The chemical and mutagenic stability of these urines at room temperature was assayed over a 14 day period. The parent compound degraded within the first seven days, but the urines remained mutagenic. Cis-platinum was chemically stable in the urine; however, the urine decreased in mutagenicity. The decrease was probably the result of stable ligands binding to the platinum.^ Inactivation methods were developed to reduce the genotoxic hazard. Urine containing cisplatin was inactivated by complexing the cisplatin with diethyldithiocarbamate (DDTC). Oxidation with NaOCl of urines containing mitomycin and doxorubicin (sodium thiosulfate must be added to the doxorubicin urine) results in mutagenic inactivation. Inactivation of urine containing cyclophosphamide requires oxidation with alkaline potassium permaganate and trapping of active degradation products with sodium thiosulfate. Urines containing these drugs can be inactivated, but not always by the same method that inactivates the drug alone in solution. Therefore, in the future development of inactivation methods, both chemical and mutagenic assays are necessary to determine effectiveness. Methods of inactivation of mutagenic excreta developed in this study are both effective and practical. ^

A case-comparison interview study of brain tumors and employment in occupations with presumed electric and magnetic field exposures

Results from epidemiologic studies suggest that persons working in occupations with presumed electric and magnetic field (EMF) exposures are at increased risk of brain cancer. This study utilized data from a completed, population-based, interview case-control study of central nervous system (CNS) tumors and employment in the petrochemical industry to test the hypothesis that employment in EMF-related occupations increases CNS tumor risk. A total of 375 male residents of the Texas-Louisiana Gulf Coast Area, age 20 to 79, with primary neuroglial CNS tumors diagnosed during the period 1980-84 were identified. A population-based comparison group of 450 age, race and geographically matched males was selected. Occupational histories and potential risk factor data were collected via personal interviews with study subjects or their next-of-kin.^ Adjusted odds ratios were less than 1.0 for persons ever employed in an electrical occupation (OR = 0.65; 95% CI = 0.40-1.09) or whose usual occupation was electrical (OR = 0.76; 95% CI = 0.33-1.73). Relative risk estimates did not increase significantly as time since first employment or duration of employment increased. Examination of CNS tumor risk by high (OR = 0.80), medium (OR = 0.88) and low (OR = 0.45) exposure categories for persons whose usual occupation was electrical did not indicate a dose-response pattern. In addition, the mean age of exposed cases was not significantly younger than that for unexposed cases. Analysis of risk by probability of exposure to EMFs showed non-significant elevations in the adjusted odds ratio for definite exposed workers defined by their usual occupation (OR = 1.78; 95% CI = 0.70-4.51) and ever/never employed status (OR = 1.54; 95% CI = 0.17-4.91).^ These findings suggest that employment in occupations with presumed EMF exposures does not increase CNS tumor risk as was suggested by previous investigations. The results of this study also do not support the EMF-tumor promotion hypothesis. ^

Exposure to nonsteroidal anti-inflammatory drugs and weight loss and hospitalization in non-small cell lung cancer patients

Background. Cancer cachexia is a common syndrome complex in cancer, occurring in nearly 80% of patients with advanced cancer and responsible for at least 20% of all cancer deaths. Cachexia is due to increased resting energy expenditure, increased production of inflammatory mediators, and changes in lipid and protein metabolism. Non-steroidal anti-inflammatory drugs (NSAIDs), by virtue of their anti-inflammatory properties, are possibly protective against cancer-related cachexia. Since cachexia is also associated with increased hospitalizations, this outcome may also show improvement with NSAID exposure. ^ Design. In this retrospective study, computerized records from 700 non-small cell lung cancer patients (NSCLC) were reviewed, and 487 (69.57%) were included in the final analyses. Exclusion criteria were severe chronic obstructive pulmonary disease, significant peripheral edema, class III or IV congestive heart failure, liver failure, other reasons for weight loss, or use of research or anabolic medications. Information on medication history, body weight and hospitalizations was collected from one year pre-diagnosis until three years post-diagnosis. Exposure to NSAIDs was defined if a patient had a history of being treated with NSAIDs for at least 50% of any given year in the observation period. We used t-test and chi-square tests for statistical analyses. ^ Results. Neither the proportion of patients with cachexia (p=0.27) nor the number of hospitalizations (p=0.74) differed among those with a history of NSAID use (n=92) and those without (n=395). ^ Conclusions. In this study, NSAID exposure was not significantly associated with weight loss or hospital admissions in patients with NSCLC. Further studies may be needed to confirm these observations.^

Profile in occupational counselling and placement and employment services: social policies axis

This paper presents the gestation of a new model of Occupational Counselling, centred in the joint action of State, Third Sector and Private Organizations. Different programmes are identified which involve the treatment of issues related to Labour, Employment and Education within the framework of objectives of social development, community participation and respect for diversity. The data of the investigation make it possible to establish connections between the tasks, professional profiles and professional training of the counsellors who participate in the different programmes.

Activity, work and employment: some reflections on a topic under debate

Since ten years ago, it is intensely thought of human work and employment in developed countries as a consequence of the deep changes on the productive system. In this chapter we analyze at first place the concept of work and its evolution, based on recent researches. In second place we review the notions of activity, work and employment and also the definition and measurement of unemployment, which is not a very old notion. The third part is about the work rol in human life and finally we study the different alternatives on activity and specific work contracts, proposals that nowadays replace the notion of "full employment" in France.

Profile in occupational counselling and placement and employment services: social policies axis

This paper presents the gestation of a new model of Occupational Counselling, centred in the joint action of State, Third Sector and Private Organizations. Different programmes are identified which involve the treatment of issues related to Labour, Employment and Education within the framework of objectives of social development, community participation and respect for diversity. The data of the investigation make it possible to establish connections between the tasks, professional profiles and professional training of the counsellors who participate in the different programmes.

Activity, work and employment: some reflections on a topic under debate

Since ten years ago, it is intensely thought of human work and employment in developed countries as a consequence of the deep changes on the productive system. In this chapter we analyze at first place the concept of work and its evolution, based on recent researches. In second place we review the notions of activity, work and employment and also the definition and measurement of unemployment, which is not a very old notion. The third part is about the work rol in human life and finally we study the different alternatives on activity and specific work contracts, proposals that nowadays replace the notion of "full employment" in France.

Profile in occupational counselling and placement and employment services: social policies axis

This paper presents the gestation of a new model of Occupational Counselling, centred in the joint action of State, Third Sector and Private Organizations. Different programmes are identified which involve the treatment of issues related to Labour, Employment and Education within the framework of objectives of social development, community participation and respect for diversity. The data of the investigation make it possible to establish connections between the tasks, professional profiles and professional training of the counsellors who participate in the different programmes.

Activity, work and employment: some reflections on a topic under debate

Since ten years ago, it is intensely thought of human work and employment in developed countries as a consequence of the deep changes on the productive system. In this chapter we analyze at first place the concept of work and its evolution, based on recent researches. In second place we review the notions of activity, work and employment and also the definition and measurement of unemployment, which is not a very old notion. The third part is about the work rol in human life and finally we study the different alternatives on activity and specific work contracts, proposals that nowadays replace the notion of "full employment" in France.

From school to work : Muslim youths' education and employment strategies in a community in Uttar Pradesh, India

India's Muslim community, which accounts for 14.4 percent of India’s vast population and is thus the largest of all religious minorities, has been the subject of considerable development discourse as Muslims have the lowest level of educational attainment and standard of living among socio-religious groups in the country. This study addresses the meaning of education and career opportunities for Muslim youths in relation to their educational credentials and social position in the hierarchy of Muslim class and caste groups, with particular reference to a community in Uttar Pradesh. The author contends that the career opportunities, possibilities, and strategies of Muslim youths in Indian society depend on multiple factors: social hierarchy, opportunities to utilize economic resources, social networks, cultural capital, and the wider structural disparities within which the Muslims are situated and wherein they question the value of higher education in gaining them admission to socially recognized and established employment sectors.

Synergistic inhibition of human cancer cell growth by cytotoxic drugs and mixed backbone antisense oligonucleotide targeting protein kinase A

Protein kinase A type I plays a key role in neoplastic transformation, conveying mitogenic signals of different growth factors and oncogenes. Inhibition of protein kinase A type I by antisense oligonucleotides targeting its RIα regulatory subunit results in cancer cell growth inhibition in vitro and in vivo. A novel mixed backbone oligonucleotide HYB 190 and its mismatched control HYB 239 were tested on soft agar growth of several human cancer cell types. HYB 190 demonstrated a dose-dependent inhibition of colony formation in all cell lines whereas the HYB 239 at the same doses caused a modest or no growth inhibition. A noninhibitory dose of each mixed backbone oligonucleotide was used in OVCAR-3 ovarian and GEO colon cancer cells to study whether any cooperative effect may occur between the antisense and a series of cytotoxic drugs acting by different mechanisms. Treatment with HYB 190 resulted in an additive growth inhibitory effect with several cytotoxic drugs when measured by soft agar colony formation. A synergistic growth inhibition, which correlated with increased apoptosis, was observed when HYB 190 was added to cancer cells treated with taxanes, platinum-based compounds, and topoisomerase II selective drugs. This synergistic effect was also observed in breast cancer cells and was obtained with other related drugs such as docetaxel and carboplatin. Combination of HYB 190 and paclitaxel resulted in an accumulation of cells in late S-G2 phases of cell cycle and marked induction of apoptosis. A cooperative effect of HYB 190 and paclitaxel was also obtained in vivo in nude mice bearing human GEO colon cancer xenografts. These results are the first report of a cooperative growth inhibitory effect obtained in a variety of human cancer cell lines by antisense mixed backbone oligonucleotide targeting protein kinase A type I-mediated mitogenic signals and specific cytotoxic drugs.