Immunological alterations induced by adjuvant treatment of postoperative colon carcinoma Duke's B or C with levamisole in combination with 5-FU.

BACKGROUND: Postoperative 5-FU combined with levamisole increases 5 year survival in colon cancer patients (Duke C) by 30% (1). In order to investigate the potential immunological mechanism, we determined lymphocyte subtypes and markers of immune activation in 22 patients before and during one year of postoperative adjuvant treatment. METHODS: Before and regularly during treatment, according to the scheme described by Moertel (1), major lymphocyte subsets were quantified by flow cytometry. Serum neopterin, soluble IL2-receptors, beta 2-microglobulin, TNF-alpha and interferon-gamma were determined by Elisa. RESULTS: The CD4/CD8 ratio increased significantly after levamisole was added to the treatment, as did the levels of soluble IL2-receptors. The percentages of T-cells expressing the interleukin 2 receptor followed a similar trend. The levels of neopterin tended to decrease during the combined treatment course. This was paralleled by a progressive fall in the proportion of T-cells expressing HLA-DR. CONCLUSIONS: The treatment induced significant and consistent alterations in major immunological mediators and lymphocyte subtypes. It remains to be established whether these changes are related to the therapeutic effect.

A simple and rapid flow cytometric method to measure lymphocyte activation in HIV+ subjects. Diminished response to pokeweed mitogen in early disease.

It was our objective to investigate the effect of asymptomatic infection with HIV on the expression of lymphocyte activation markers after stimulation with mitogens. Whole blood cultures were made of HIV+ and HIV- subjects (29 asymptomatic HIV-1-infected subjects and 33 apparently healthy normal volunteers). At various times after stimulation with concanavalin A (Con A), anti-CD3 and pokeweed mitogen (PWM), the expression of activation markers (CD25 and HLA-DR) and the blastogenesis were quantified by flow cytometry. The flow cytometric quantification of the expression of activation markers and blastogenesis in whole blood cultures provided an easy and safe alternative to thymidine incorporation to assess lymphocyte responses in HIV+ subjects. Activation showed a tendency to be lower in the HIV+ subjects with all three stimulants. This difference with HIV- subjects was statistically significant only for stimulation with PWM after 4 days. Further investigations should be undertaken to show whether this functional impairment is related to disease progression and whether it can be influenced by effective therapy.

Levamisole plus 5-fluorouracil inhibits the growth of human colorectal xenografts in nude mice.

Fragments of human colorectal adenocarcinomas were inserted under the renal capsule of nude mice. The growth of these tumour grafts was significantly inhibited by the combination of 5-fluorouracil (5-FU) and levamisole. An alternating regimen of levamisole 2.5 mg/kg and 5-FU 20 mg/kg decreased the size of tumour implants by 33-59% and/or increased the number of macroscopically disappeared fragments in the combined group compared with ineffective monotherapy with saline, levamisole or 5-FU. This model could be valuable for investigating the mechanism of action of levamisole and to evaluate the effects of this adjuvant therapy in other oncological settings.

The effects of short-term treatment with levamisole on cytokines in volunteers and cancer-patients.

In search for clues to the potential immunomodulating mechanism of action of levamisole which might be used as monitoring parameters, we have determined a variety of cytokines in the peripheral blood of volunteers and carcinoma patients before and after a single or a 3-day-treatment with 150 mg/day. In cancer patients no changes could be detected 4 days after a 3-day-treatment course in the levels of TNF-alpha, IL-1beta, IL-2 or IL-6. In a placebo-controlled volunteer study the same treatment did not affect the levels of beta2-microglobulin, IL-1beta, IL-1alpha, IL-2 or IL-6. However, 24hr after the last treatment the concentration of neopterin was slightly but significantly increased and the concentration of soluble IL-2 receptors decreased. A single treatment failed to produce such an effect. It is suggested that the measurement of neopterin and soluble IL-2 receptors may provide useful information in future trials.

Antitumoral effects of R 75251 on the growth of transplantable R3327 prostatic adenocarcinoma in rats.

The antitumoral activity of a novel imidazole derivative, R 75,251, has been studied in the androgen-dependent R3327G Dunning prostate adenocarcinoma grafted subcutaneously in syngeneic rats. Dietary application resulting approximately in dose levels of 80, 120, and 160 mg/kg reduced tumor weight by 66, 81, and 79%, respectively. This effect was not significantly different from that measured after castration (-82%). In intact animals, however, serum testosterone levels were almost not affected by R 75,251 treatment while LH levels rose two- to threefold. In castrated rats a tenfold increase in LH was observed. Moreover, prostate and seminal vesicles weights decreased much less after R 75,251 treatment than after castration. In castrated animals, treatment with R 75,251 induced a slight, non-significant reduction in tumor weight (-36%) compared with castration alone. In castrated animals, tumor growth was restored by exogenous administration of testosterone. In such animals R 75,251 also significantly reduced tumor weight by 57%. Similar results were obtained with Dunning R3327G prostate adenocarcinoma grafted beneath the renal capsule in male syngeneic rats receiving twice daily orally by gavage a dose of 80 mg/kg of R 75,251. These data suggest that R 75,251 exerts an antitumoral effect independent of its inhibition of androgen biosynthesis.