Human ovarian-carcinoma cell lines and companion xenografts: a disease-oriented approach to new platinum anticancer drug discovery

Summary A disease-oriented approach to the discovery of novel platinum anticancer drugs has been established through the setting up of parallel human ovarian-carcinoma cell lines and xenografts. The correlation between in vitro and in vivo antitumour activity was determined for four reference platinum agents (cisplatin, carboplatin, iproplatin and tetraplatin) in eight companion lines. Two methods of assessing antitumour effect were used in vitro (tritiated thymidine incorporation and sulforhodamine B staining) and three were applied in vivo [28-day treated/control (T/C) ratio, growth delay and specific growth delay]. In vitro, large differences in cytotoxicity across the cell lines were observed for each drug. This was also reflected in the xenografts for cisplatin and carboplatin and, to a lesser extent, for iproplatin. A correlation analysis of in vitro vs in vivo data revealed a high, statistically significant positive correlation for cisplatin and a strong positive correlation for carboplatin. However, for the two platinum(IV) drugs, the correlation was less good. In particular, tetraplatin was markedly less active in vivo (showing a general lack of activity against all of the tumour lines) than its in vitro potency against the cell lines predieted, resulting in poor correlation coefficients. These human tumour panels may be valuable for the elucidation of both cellular/molecular and corresponding in vivo pharmacological mechanisms of platinum drug resistance. Moreover, the HX/62 and SKOV-3 tumour lines, which exhibit a level of intrinsic resistance to the four reference agents both in vitro and in vivo (and which were derived from patients who had not received prior platinum therapy), represent particularly useful evaluation models for the discovery of novel broad-spectrum platinum drugs.This study was supported by grants to the Institute of Cancer Research from the Cancer Research Campaign and the Medical Research Council, the Johnson Matthey Technology Centre and Bristol Myers Squibb Oncology     

Nasal polyposis: prevalence of positive food and inhalant skin tests.

OBJECTIVES: To investigate the etiology of nasal polyps and its relationship to allergy. The prevalence of positive food and inhalant skin tests in patients with nasal polyps and nonatopic controls was compared. STUDY DESIGN AND SETTING: Prospective controlled study in tertiary referral rhinology clinic. RESULTS: Seventy percent (70%) of the patients with nasal polyps had positive skin tests to an average of four foodstuffs, compared to 34 percent of controls (P = 0.006). Only 35 percent of the nasal polyp patients also had positive inhalant skin tests. Overall, the prevalence of positive inhalant skin tests was similar in the nasal polyp patients and controls. CONCLUSIONS: These findings suggest that the positive skin tests to foods are not merely a reflection of the general atopic status of patients with nasal polyps. It may be that non-IgE-mediated hypersensitivities, such as to ingested foods, play a role on the basis of a significant number of patients with positive intradermal skin tests to foods. SIGNIFICANCE: Evaluation of the allergic status of patients with polyposis is important. Dietary manipulation may be indicated, though its role needs further investigation.     

The prevalence of airways hyperresponsiveness in members of an exercise training facility.

Athletes have a high prevalence (11-50%) of exercise-induced asthma, which may be caused by the hyperventilation accompanying repetitive bouts of strenuous exercise. We hypothesized that recreational exercisers would display a similar trend. Eucapnic voluntary hyperventilation (EVH) bronchoprovocation (breathing 21% O2, 5% CO2, and 74% N2 at 60% of MVV for 5 minutes) was performed to determine the prevalence of airways hyperresponsiveness (AHR) in adults (n=212, 146 males, mean +/- standard deviation, age 32 +/- 10 years) who exercised regularly (10 +/- 10 years, 31 +/- 28% of their lives): none had a previous diagnosis of asthma. AHR was defined by at least a 10%, 20%, or 25% decline in FEV1, FEF(25-75), or PEFR, respectively, by spirometry at 1, 5, 10, and 15 minutes post-EVH. Forty-one of 212 (19%) tested positive for AHR: 20 of 41 (49%) were positive by FEV1, 28 of 41 (68%) by FEF(25-75), and 27 of 41 (66%) by PEFR. Comparing responders with nonresponders: pre-EVH lung function was equivalent, except for FEV1, which was reduced (p<0.05) in responders (96 +/- 13 vs. 102 +/- 12% predicted). Mean maximal negative deflections for responders were: for FEV1, -17 +/- 7%; FEF(25-75), -31 +/- 10%; PEFR, -38 +/- 11%. Ranges of decline for responders were: FEV1, -10 to -33%; FEF(25-75), -20 to -59%; PEFR, -25- to -70%. We conclude that in these regular exercisers, the prevalence of AHR is high and comparable with some athletic populations.     

Anxiety and hippocampus volume in the rat.

In depressed patients as well as healthy controls, a positive relationship between hippocampal volume and trait anxiety has been reported. This study sought to explore the possible inter-relation between hippocampal volume and trait anxiety further. Magnetic resonance imaging at 7 T was used to measure hippocampal volumes in a rat model of extremes in trait anxiety (experiment 1) and in a Wistar population with normal anxiety-related behavior (experiment 2). In addition to anxiety-related behavior, potentially confounding factors (depression-like, exploratory, and locomotor behavior) were assessed. Experiment 1 globally supported the hypothesis of a positive relationship between hippocampus volume and trait anxiety but did not allow for ruling out possible confounds arising from cosegregation of other behavioral traits. Experiment 2 yielded strong evidence for a negative relationship which was specific for trait anxiety. Thus, the relationship between hippocampal volume and anxiety may be more complex than expected. Interestingly, anxiety-related behavior in experiment 2 had a stronger influence on hippocampal volume than depression-like behavior. In the light of hippocampal volume loss in anxiety disorder and frequent comorbidity of anxiety and depression, this finding suggests that further research into the relationship between anxiety and hippocampal volume may be critical for understanding hippocampal contributions to normal and pathological behavior.