Inhibition of RNA polymerase and formyltetrahydrofolate synthetase activity by 6-chloro-8-aza-9-cyclopentylpurine. Structure-activity relationships

The structural requirements for inhibition of bacterial RNA polymerase and rabbit liver formyltetrahydrofolate synthetase activity by a series of purine nucleoside analogs related to 6-chloro-8-aza-9-cyclopentylpurine (689) were investigated. To achieve an inhibitory effect, preincubation of the enzyme preparations with the purine analogs, prior to assay of enzyme activity, was required. The greatest inhibition was produced by analogs containing all three alterations of the purine nucleoside structure: the 6-halo, 8-aza, and 9-cyclopentyl groups. It is suggested that 689 inhibits the activity of enzymes involved in nucleic acid synthesis by a site-directed alkylation.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/32772/1/0000143.pd

In vivo bioluminescence imaging of locally disseminated colon carcinoma in rats

Animal tumour models using orthotopic tumours for the evaluation of cancer therapies are of greater clinical relevance than subcutaneous models, but they also pose greater difficulties for measuring tumour size and quantifying response to treatment. In this study, we used noninvasive bioluminescence imaging to monitor the intraperitoneal growth of luciferase-transfected CC531 colorectal cells in adult WAG/RIJ rats. The bioluminescence signal correlated well with post-mortem assessment of tumour load by visual inspection of the peritoneal cavity at specific follow-up times. Using bioluminescence imaging, we were able to monitor peritoneal tumour growth sequentially in time and to calculate a tumour growth rate for each animal; this is not possible with invasive methods of evaluating tumour load. Bioluminescence imaging of rats treated with a single dose of cisplatin (4 mg x kg(-1), i.p.) demonstrated a significant delay in peritoneal tumour growth relative to saline controls (mean 45.0+/-s.d. 13.0 vs 28.2+/-10.3 days; P=0.04). Similar protocols evaluated by visual scoring of tumour load at 40 days after inoculation supported these findings, although no quantitative assessment of treatment-induced growth delay could be made by this method. This study shows that in vivo imaging of luciferase-transfected tumour cells is a useful tool to investigate the dynamics of disseminated tumour growth and efficacy of anticancer treatment in orthotopic models of peritoneal cancer in rats. It offers an attractive alternative to invasive methods, and requires fewer animals for measuring tumour response to therapy

Radioimmunotherapy Improves Survival of Rats with Microscopic Liver Metastases of Colorectal Origin

BACKGROUND: Half of the patients with colorectal cancer develop liver metastases during the course of their disease. The aim of the present study was to assess the efficacy of radioimmunotherapy (RIT) with a radiolabeled monoclonal antibody (mAb) to treat experimental colorectal liver metastases. METHODS: Male Wag/Rij rats underwent a minilaparotomy with intraportal injection of 1 x 10(6) CC531 tumor cells. The biodistribution of (111)In-labeled MG1, 1 day after intravenous administration, was determined in vivo and compared with that of an isotype-matched control antibody (UPC-10). The maximal tolerated dose (MTD) of (177)Lu-labeled MG1 was determined and the therapeutic efficacy of (177)Lu-MG1 at MTD was compared with that of (177)Lu-UPC-10 and saline only. RIT was administered either at the day of tumor inoculation or 14 days after tumor inoculation. Primary endpoint was survival. RESULTS: (111)In-MG1 preferentially accumulated in CC531 liver tumors (9.2 +/- 3.7%ID/g), whereas (111)In-UPC-10 did not (0.8 +/- 0.1%ID/g). The MTD of (177)Lu-MG1 was 400 MBq/kg body weight. Both the administration of (177)Lu-MG1 and (177)Lu-UPC-10 had no side-effects except a transient decrease in body weight. The survival curves of the group that received (177)Lu-UPC-10 and the group that received saline only did not differ (P = 0.407). Administration of (177)Lu-MG1 RIT immediately after surgery improved survival significantly compared with administration of (177)Lu-UPC-10 (P = 0.009) whereas delayed treatment did not (P = 0.940). CONCLUSION: This study provides proof of principle that RIT can be an effective treatment modality for microscopic liver metastases, whereas RIT is not effective in larger tumors

Conflict at work: basic principles and applied issues

Conflict at work is quickly classified as a "darkside" construct that has primarily negative, destructive, and aversive consequences to individual employees’ well-being and task performance, to citizenship behavior and performance in work teams, and to organizational fitness and survival chances. In this chapter, I review these and related research findings and examine under what conditions, and why, conflict tends to be primarily negative and destructive or, alternatively, positive and constructive. Questions that are asked and answered include "does it matter what the conflict is about?" and "to what extent does the way people manage their conflicts bring out positive and/or negative consequences?" and "what can be done, in terms of systems design, or training and development, to benefit from conflict at work and to put it to good use?" In addition to a closer examination of the possible functions of conflict at work, this chapter devotes a large section to conflict management. This chapter starts with a brief but necessary treatment of some definitional aspects, to set the stage and to clarify some issues left unclear in past work on organizational conflict. From this it follows, among other things, that this chapter is not about intrapersonal conflicts, in which an individual needs to decide between two equal positives or negatives—as in so-called decisional conflicts, role conflicts, or work-family conflicts. Also, it clarifies that social conflict needs to be distinguished from other "dark-side" constructs that plague organizations, including aggression, incivility, and deviance. Although these constructs are touched on, it is important to reemphasize that conflict need not involve intent to harm another party and need not cause negative outcomes . The second major section of this chapter is about conflict-management tendencies and practices, relating research to core theories of strategic choice such as Deutsch’s (1973) theory of cooperation and competition and Pruitt and Rubin’s (1986) dual concern theory. The section ends with a relatively brief treatment of Organizational Dispute Resolution (ODR) systems and more informal dispute resolution strategies applied by managers and organizational leaders. The third section explores the various functions, both positive and negative, of conflict at work. The fourth and final section concludes the chapter with some core conclusions, with a specific eye toward applied issues and possible advice to practitioners faced with conflicts in their workplace