Insights into Mechanisms of Cisplatin Resistance and Potential for Its Clinical Reversal

Cisplatin in combination with other cytotoxic agents is the backbone for a potential cure of testicular germ cell neoplasms and is a critical factor in the substantial activity observed in the treatment of small cell lung cancer, bladder cancer, and ovarian germ cell tumors. Resistance to cisplatin at the onset of treatment or at relapse limits its curative potential, however. Laboratory studies using both cells selected for cisplatin resistance by exposure to sublethal concentrations and biopsy specimens from patients' tumors provide insights for the potential mechanisms of resistance. The mechanisms identified in vitro include a complex and wide array of related and unrelated pathways such as alterations in cellular drug transport, enhanced DNA repair dependent and independent of signal transduction pathways, and enhanced intracellular detoxification such as glutathione and metallothionein systems. Studies of these mechanisms have identified a number of agents with known potential for administration to humans and that reverse cisplatin resistance in vitro; for example, reversal of cellular accumulation defects by dipyridamole; inhibition of DNA repair by hydroxyurea, pentoxifylline, and novobiocin; inhibition of the glutathione system by ethacrynic acid and buthionine sulfoximine; and inhibition of signal transduction pathways by cyclosporine, tamoxifen, and calcium channel-blocking agents. Current phase I clinical trials are focusing on the most effective doses and schedules to administer these agents in combination with cisplatin. Initial uncontrolled trials in limited numbers of patients suggest that the addition of modulators of cisplatin has the potential to reverse resistance in patients previously failing therapy. Another promising avenue for circumventing cisplatin resistance is the development of noncross-resistant platinum analogs.     

The Perceived Influence of Clinical Pharmacy Services on Physician Prescribing Behavior: A Matched-Pair Comparison of Pharmacists and Physicians

In contrast with cross-sectional designs used in previous studies, this exploratory study compared survey data from 127 matched pairs of clinical pharmacists and physicians working together. Physicians' perceptions of the importance of clinical pharmacy activities for patient care and the competence of pharmacists performing the activities were examined for their influence on prescribing behavior in an institutional setting. Data from a national survey showed that physicians rated pharmacists higher regarding recommendations based on drug use evaluations (p = 0.004) and competency to provide all clinical pharmacy services. Scores for pharmacokinetics ratings were similar between pharmacists and physicians (p = 0.168). Pharmacists rated the importance of recommendations based on cost-effectiveness higher than physicians (p = 0.012). Overall, physicians' perceptions of activity importance for patient care and pharmacist competency appear to dictate pharmacists' influence on physician prescribing behavior (R = 0.723).     

Pharmaceutical Marketing: Implications for Medical Residency Training

An educational intervention was developed to improve family practice residents' ability to obtain useful information from pharmaceutical representatives. The curriculum is based on the traditional one-on-one drug detail. The objectives are to develop residents' skills in controlling the interview, promote skills for critically analyzing drug-promotional material, and discuss ethical issues. The contents include an assessment tool, suggested readings, and interview questions with rationale. After 5 years, residents' confidence in all areas of the curriculum improved significantly.     

Alpha-melanocyte-stimulating hormone reduces endotoxin-induced liver inflammation.

Alpha-Melanocyte-stimulating hormone (MSH) is a potent anti-inflammatory agent in many models of inflammation, suggesting that it inhibits a critical step common to different forms of inflammation. We showed previously that alpha-MSH inhibits nitric oxide (NO) production in cultured macro-phages. To determine how alpha-MSH acts in vivo, we induced acute hepatic inflammation by administering endotoxin (LPS) to mice pretreated with Corynebacterium parvum, alpha-MSH prevented liver inflammation even when given 30 min after LPS administration. To determine the mechanisms of action of alpha-MSH, we tested its influence on NO, infiltrating inflammatory cells, cytokines, and chemokines. Alpha-MSH inhibited systemic NO production, hepatic neutrophil infiltration, and increased hepatic mRNA abundance for TNF alpha, and the neutrophil and monocyte chemokines (KC/IL-8 and MCP-1). We conclude that alpha-MSH prevents LPS-induced hepatic inflammation by inhibiting production of chemoattractant chemokines which then modulate infiltration of inflammatory cells. Thus, alpha-MSH has an effect very early in the inflammatory cascade.     

Changes in the Subcellular Distribution of the Rat Uterus Oestrogen Receptor as Induced by Oestradiol,Tamoxifen and ZD 182,780

The aim of this work was to compare the subcellular distribution of the oestrogen receptor from the uteri of rats treated with vehicle alone (control group), oestradiol or one of the antio-estrogenic drugs tamoxifen and ZD 182,780. The nuclear, microsomal and cytosolic oestrogen receptor contents were evaluated by an immunoenzymatic method (“ER-EIA” kit from Abbott Laboratories) and the results in each fraction were expressed as a percentage of the total number of receptors. Parallel studies were performed to assess the uterotrophic effect of these drugs and to assess that they had reached the uterus. In the control group, we found that the oestrogen receptor was distributed mainly between the microsomal (29.1 ± 1.3%) and cytosolic (68.1 ±0.9%) fractions, with only a small amount located in the nucleus (2.8 ± 0.5%). When oestradiol was administered, the oestrogen receptor distribution was: nuclear 11.7 ± 2.0, microsomal 15.5 ± 1.3 and cytosolic 72.8 ± 3.3% and, in the tamoxifen group, the results were: nuclear 18.5 ± 1.5, microsomal 26.0 ± 31 and cytosolic 55.5 ± 3.4%, which shows a relative shift both to the control and the oestradiol-treated groups. In the uteri of rats treated with ZD 182,780 the results were very similar to those obtained in the control group. Our results indicate that the subcellular distribution of the oestrogen receptor varies according to the drug administered and that this receptor may not be located in a single subcellular compartment. Moreover, the nuclear uptake of the ZD 182,780-oestrogen receptor complex seems to be blocked, possibly due to impaired receptor dimerization. In the case of tamoxifen, the intracellular transport of the receptor also seems to be blocked, probably due to the nuclear retention of the receptor, thus suggesting that tamoxifen must impair the oestrogen receptor function on a step subsequent to the receptor dimerization.     

Differential distribution of N-acetylaspartylglutamate and N-acetylaspartate immunoreactivities in rat forebrain

Summary Contradictory immunohistochemical data have been reported on the localization of N-acetylaspartylglutamate in the rat forebrain, using different carbodiimide fixation protocols and antibody purification methods. In one case, N-acetylaspartylglutamate immunoreactivity was observed in apparent interneurons throughout all allocortical and isocortical regions, suggesting possible colocalization with GABA. In another case, strong immunoreactivity was observed in numerous pyramidal cells in neocortex and hippocampus, suggesting colocalization with glutamate or aspartate. Reconciling these disparate findings is crucial to understanding the role of N-acetylaspartylglutamate in nervous system function. Antibodies to N-acetylaspartylglutamate and a structurally related molecule, N-acetylaspartate, were purified in stages, and their cross-reactivities with protein conjugates of N-acetylaspartylglutamate and N-acetylaspartate were monitored at each stage by solidphase immunoassay. Reduction of the cross-reactivity of the anti-N-acetylaspartylglutamate antibodies to N-acetylaspartateprotein conjugates to about 1% eliminated significant staining of most pyramidal neurons in the rat forebrain. Utilizing highly purified antibodies, the distributions of N-acetylaspartylglutamate and N-acetylaspartate were examined in several major telencephalic and diencephalic regions of the rat, and were found to be distinct. N-acetylaspartylglutamate-immunoreactivity was observed in specific neuronal populations, including many groups thought to use GABA as a neurotransmitter. Among these were the globus pallidus, ventral pallidum, entopeducular nucleus, thalamic reticular nucleus, and scattered non-pyramidal neurons in all layers of isocortex and allocortex. N-acetylaspartate-immunoreactivity was more broadly distributed than N-acetylaspartylglutamate-immunoreactivity in the rat forebrain, appearing strongest in many pyramidal neurons. Although N-acetylaspartate-immunoreactivity was found in most neurons, it exhibited a great range of intensities between different neuronal types.     

The nature of the head and neck cancer

Summary Squamous cell carcinoma of the head and neck is a disease predominantly of males and is due to a variety of known environmental irritants, notably cigarette smoke. Dietary, viral and immunological factors may also be relevant. Head and neck squamous cancers express epidermal growth factor receptors and some show weak levels of oestrogen receptor activity, but a reliable serum marker of tumour burden remains to be identified. The prognosis is found to be less favourable in females, in those with advanced T stage, in association with multiple node involvement, especially where extracapsular spread is present and where the T4/T8 ratio is elevated. Administration of heterologous blood during therapy may also have an adverse effect on prognosis. Interested clinicians must remember that most cases are preventable. Correspondence to: A.G.D. Maran