Beta-Carotene, vitamin A, and lung cancer chemoprevention: results of an intermediate endpoint study.

A randomized, placebo-controlled clinical trial of beta-carotene and retinol was conducted with 755 former asbestos workers as study subjects. The targeted endpoint for the intervention study was a reduction in the incidence and prevalence of sputum atypia. The dosage of 50 mg beta-carotene/d and 25,000 IU retinol/d on alternate days resulted significant increases in serum concentrations of both agents with no clinically significant toxicity. Skin yellowing was observed in approximately 35% of patients and may have contributed adversely to protocol adherence. Baseline analysis revealed that smoking and drinking were associated with lower concentrations of serum beta-carotene, even after dietary carotene intake was adjusted for (P < 0.0001). Baseline concentrations of retinol were apparently lowered by smoking (P < 0.002) and increased by drinking (P < 0.0001). Drinking and smoking also were significantly related to lower beta-carotene concentrations after supplementation (P < 0.001). No significant reduction in sputum atypia was observed after treatment.

Two biochemical markers effectively used to separate smokeless tobacco users from smokers and nonusers.

Data from asbestos workers were used to devise a cutpoint classifier to identify subjects as Nonuser (non-tobacco user), Smokeless (exclusive smokeless tobacco user), and Smoker (ignited tobacco user). In some clinical trials and smoking cessation programs, Smokeless should be separated from Smoker. One therefore needs a marker for smoke exposure, such as thiocyanate, since nicotine levels, as measured by cotinine, could be similar in both groups. Levels of cotinine (ng/mL) and thiocyanate (mumol/L) levels (mean +/- SD) were, respectively: 320.9 +/- 201.1 and 145.9 +/- 63.7 for the Smoker group; 339.1 +/- 327.5 and 32.0 +/- 16.9 for the Smokeless group; and 0.6 +/- 2.6 and 58.2 +/- 33.2 for the Nonuser group. For Nonuser, Smokeless, and Smoker, respectively, the self-reported status was 45.1%, 10.8%, and 44.1%, which was adjusted to 42.2%, 11.6%, and 46.2%; the classifier yielded sensitivities of 100%, 76.1%, and 92.2%; specificities of 96.1%, 97.6%, and 96.4%; and predictive values of 94.9%, 80.6%, and 95.6%. The classifier successfully identified Nonusers, separated Smokeless from Smoker, and determined the prevalence of false reports in our cohort.

A novel morphine sulphate preparation: clinical trial of a controlled-release morphine suspension in cancer pain.

In order to determine the efficacy of a novel controlled-release morphine suspension, we performed two prospective sequential open-label studies in patients with pain due to cancer. The studies were identical except for the duration of treatment (three days and 30 days respectively). Sixty-nine patients with a variety of advanced cancers and associated pain participated. Fifty-three patients completed the trials, 38 on the three-day trial and 15 on the 30-day trial. In both groups the amount of morphine required to obtain pain relief was initially established using controlled-release morphine tablets and immediate-release morphine for 'rescue' dosing. Patients were begun on equivalent doses of the study drug in place of the controlled-release tablets. No differences in pain score or the amount of 'rescue' morphine were noted following the switch to the controlled-release morphine suspension. Toxicity was as anticipated for the use of morphine in this situation and no adverse effects were observed during administration of the suspension. These data suggest that this new formulation of morphine is equipotent to conventional controlled-release morphine tablets and provides pain relief for a 12-hour dosing interval. This novel morphine formulation could be especially useful for paediatric patients and for those who have difficulty in swallowing.

Direct antiproliferative effects of cyclosporin A on murine lymphoreticular tumor cells in culture.

Cyclosporin A (CSA) has been shown to prevent mouse spleen cell blast formation in response to concanavalin A (con A) and to inhibit lymphocyte proliferation. In the presence of interleukin-2 (IL-2), however, the proliferation of preformed blasts is not affected by CSA. We examined the effects of CSA on the growth in culture of several established mouse lymphoreticular tumor-cell lines proliferating independently of exogenous lymphokines. We found that CSA abolished, by direct cytolysis, growth of the T-lymphoma lines, EL4, WEHI22.1, S49.1, RL male 1, WR19L, and YAC. In contrast, growth of the non T-cell lines, S49, P388D1, RAW264.7, PU51.R, P815, P3X63Ag8, and L929, was variably retarded by a noncytocidal action of CSA. The concentration of CSA required for T-cell cytolysis was relatively high and directly related to the numbers of cells treated. Expression of Thy-1 antigen predicted for the susceptibility of a cell line to CSA-induced lysis. At the concentrations used there was no evidence of significant mitotic death following CSA treatment; cells previously exposed to CSA and then washed were able to resume a delayed but otherwise normal pattern of replication. In a preliminary experiment, CSA afforded significant protection to C57BL/6 mice transplanted with syngeneic EL4 cells. The results indicate that CSA, in vitro and in vivo, is a potent antiproliferative agent selective for T cells, and that in the absence of growth factors its inhibitory effects are not limited to early event(s) in the T-cell activation process.

Cyclosporin a inhibits T cell-mediated augmentation of mouse natural killer activity.

Cyclosporin A (CSA) in vitro inhibited the spontaneous cytotoxic activity of mouse spleen cells against YAC target cells in a 4 hr 51Cr release assay. While natural killer (NK) cells were inhibited directly by CSA, these suppressive effects were largely reversible by coculture of effector cells for an optimal period with polyinosinic-polycytidylic acid (Poly I:C) or lipopolysaccharide (LPS). In contrast concanavalin A (Con A), in the presence of CSA, was unable to augment NK activity. The supernatant, however, of mouse spleen cells cultured with Con A was fully able to augment the NK the activity by freshly cultured spleen cells in the presence of CSA. The results indicate that CSA inhibits NK activity by two distinct mechanisms: a) a direct inactivation of NK cells and b) a suppression of production or release of an NK-activating factor from T cells, but not B cells or macrophages.

Inhibition of mouse natural killer activity by cyclosporin A.

Cyclosporin A(CSA), administered in vivo or in vitro, inhibited the spontaneous cytotoxicity of C57BL/6 and NZB/WF1 mouse spleen cells against YAC and K562 target cells in a 4 hr 51Cr release assay. Inhibition of natural killing (NK) by CSA occurred rapidly, was dose-dependent, and did not require the presence of T cells, B cells or macrophages. CSA depressed NK activity by direct interaction with NK cells. There was no evidence that inhibition of NK by CSA was mediated through suppressor cells.