Bisdioxopiperazine, (+)-1,2-bis(3,5-dioxopiperazinyl-1-yl)propane (ICRF 187), enhances the antiproliferative effect of cisplatin on human ovarian cancer cells.

The bisdioxopiperazine ICRF 187 is a potent intracellular chelating agent which effectively diminishes Adriamycin cardiotoxicity without compromising its antitumor activity. Our study aimed at verifying whether ICRF 187 can modulate the cytotoxic action of cisplatin (CDDP) on ovarian cancer cells. We used the A2780 ovarian cancer cell line and a subline resistant to CDDP (A2780-CDDP) obtained in our laboratory by continuous exposure of the parenatal cells to progressively increasing CDDP doses. In both cell lines ICRF 187 (0.1-0.5 microgram/ml) used in combination with CDDP (0.01-1 microgram/ml) produced a dose-dependent reduction of CDDP IC50 (the concentration inhibiting 50% of cell growth). Moreover, when ICRF 187 was used in combination with CDDP, analysis of the data by the isobole method showed that the combination of the two drugs produced a synergistic antiproliferative activity in both cell lines, with a CDDP potentiation up to fivefold. Our in vitro data show that ICRF 187 can synergize with CDDP. Prospective clinical trials are now needed to verify whether the addition of ICRF 187 to CDDP-containing regimens will result in an improved clinical response in ovarian cancer.

Adjuvant effect of low-dose interleukin-2 on antibody response to influenza virus vaccination in healthy elderly subjects.

It is well known that immune efficiency is frequently deteriorated in elderly people. The age-diminished antibody response to T-cell dependent antigens, such as influenza virus antigens, may explain the low protection offered by influenza vaccination in the elderly population. To investigate the possibility of increasing the antibody response to influenza virus vaccinations, we have conducted a nursing home-based study on the efficacy of IL-2. Seventy-five institutionalized elderly subjects (82 +/- 8 years) were enrolled in the study in the course of winter season 1991-1992. Thirty-nine subjects were treated with three subcutaneous daily injections of interleukin-2 (IL-2, 1 x 10(6) I.U./day) before vaccination and their antibody response was compared to that of 36 aged people receiving the vaccine only. An increased antibody response against influenza virus was present in vaccine plus IL-2 treated subjects (P < 0.001) but not in subjects treated with vaccine only. The number of protected subjects 45 days after vaccination was increased only in the IL-2-treated group (P = 0.045). The low-dose of IL-2 administered and the short-term treatment allowed a good tolerance to the IL-2 injection. In conclusion, the low-dose IL-2 treatment represents an effective means of inducing antibody response to influenza virus antigens in elderly subjects without appreciable toxicity.

A randomized study of low-dose interleukin-2 subcutaneous immunotherapy versus interleukin-2 plus interferon-alpha as first line therapy for metastatic renal cell carcinoma.

AIMS AND BACKGROUND: IL-2 given subcutaneously in combination with interferon-alpha 2b (IFN) appears to induce a response rate comparable to that obtained with IL-2 intravenous injection in patients with metastatic renal cell carcinoma (RCC) but with lower toxicity. The role of IFN when combined with IL-2 has however still to be defined. The present study was performed to draw some preliminary conclusions about the effect of IFN in combination with IL-2 in metastatic RCC. METHODS: The study included 30 consecutive patients with metastatic RCC who were randomized to treatment with IL-2 subcutaneous therapy (3 million IU twice/daily for 5 days/week for 6 weeks) or with IL-2 plus IFN (5 million U/m2 subcutaneously thrice weekly). In patients without progressive disease, a second cycle was repeated after a 28-day rest period. RESULTS: No significant difference in partial response rate was found between patients treated with IL-2 alone and those given IL-2 plus IFN (5/15 vs 4/15). Similarly, no difference was seen in the percentage of stable disease (7/15 vs 7/15). Toxicity was higher in patients who received IL-2 plus IFN. Lymphocyte and eosinophil mean increase was higher in patients treated with IL-2 alone than in those treated with IL-2 plus IFN, without however any significant difference. CONCLUSIONS: The present results, which require confirmation in a larger series, indicate that combination with IFN does not increase the efficacy of IL-2 subcutaneous immunotherapy in metastatic RCC but only the toxicity of treatment.

5-Methylcytosine content of DNA in blood, synovial mononuclear cells and synovial tissue from patients affected by autoimmune rheumatic diseases.

The percentage of 5-methylcytosine (m5Cyt) has been determined in peripheral blood, synovial mononuclear cells and synovial tissue from patients affected by various rheumatic autoimmune diseases. The determination was performed by reversed-phase high-performance liquid chromatography. Fifteen controls were compared to twenty-one patients affected by rheumatoid arthritis and to nine patients affected by systemic lupus erythematosus. The mean percentage of m5Cyt in normal individuals was significantly higher than in the rheumatoid arthritis and systemic lupus erythematosus patients. In addition, patients with active disease showed lower values than patients in remission. This finding is in agreement with the hypothesis that DNA hypomethylation may play a role in the pathogenesis of the autoimmune diseases, resulting in altered oncogene expression. Therapy with cyclosporin A led to a decrease in the percentage of m5Cyt in three rheumatoid arthritis patients, but a rebound was observed when the cyclosporin A was suspended. The percentage of m5Cyt in the DNA of synovial tissue from four rheumatoid arthritis patients and five patients with osteoarthritis was similar; this observation confirms that, in addition to disease-specific and disease activity-specific variations, the percentage of m5Cyt may also show tissue-specific variations.

Tenoxicam and ketoprofen level monitoring with high performance liquid chromatography in patients affected by rheumatoid arthritis.

A new reversed-phase high-performance liquid chromatography (HPLC) technique was employed in order to monitor the plasma Tenoxicam (TNX) levels in 13 patients affected by rheumatoid arthritis who were participating in a short-term, controlled, randomized, double-blind TNX (20 mg once a day) vs Ketoprofen (KPF) study. The HPLC method described by Sutterwhite was used to measure the KPF levels in plasma samples from 10 rheumatoid patients assigned to the treatment with this drug (100 mg twice a day). The mean (+/- 1 SD) steady-state plasma TNX concentration was 11.138 +/- 3.55 micrograms/ml. Twelve out of 13 patients had a drug level within the steady-state range and 8 out of these 12 patients showed clinical improvement. A synovial fluid TNX concentration slightly lower than plasma levels (11.04 vs 13.58 micrograms/ml), and TNX synovial tissue levels remarkably lower than plasma levels (1.02 vs 3.5 and 0.85 vs 4.1 micrograms/ml) were observed in three further rheumatoid patients. The mean plasma concentration of KPF (+/- 1 SD) was 3.23 +/- 2.68 micrograms/ml and only two patients showed drug levels within the therapeutic range. In some cases the lack of compliance with the treatment regimen was proved in both groups, and an explanation for the poor efficacy of the drug was provided. A positive clinical result was reached in some of the patients with low drug plasma levels, in both the TNX and KPF groups. Gastrointestinal side-effects were observed in 4 patients from both groups, 2 within the therapeutic range and 2 below. This finding confirms that several variables, in addition to the plasma drug concentration, condition the efficacy and side-effects of an NSAID.

Interleukin-2, soluble interleukin-2 receptor and tumor necrosis factor in sera from patients with rheumatoid arthritis.

Interleukin-2 (IL-2), soluble interleukin-2 receptor (IL-2R) and tumor necrosis factor (TNF) have been measured in sera from 47 patients affected by classic rheumatoid arthritis (RA) using an enzyme-linked immunosorbent assay. The patients were divided into 4 groups as follows: group A, 18 patients with inactive disease; group B, 19 patients with active disease under treatment with non-steroidal antiinflammatory drugs (NSAID) and second-line drugs; group C, 5 patients with active disease under treatment with NSAID and cyclosporine A (CSA) for at least 4 months; group D, 5 patients in the same condition as patients of group C, but treated with azathioprine (AZA) instead of CSA. IL-2 was undetectable in all patients except two, both characterized by active disease. Soluble IL-2R levels were above the upper limit of the normal range in most of the patients studied, but the mean value ( +/- 1 SD) was significantly higher in patients of group B (1,288 +/- 421 U/ml) than in patients of group A (686 +/- 205 U/ml) and group C (842 +/- 414 U/ml). In two patients affected by active RA treated with pulse methylprednisolone therapy (1 g/day for 3 alternate days) the values of soluble IL-2R dropped from 948 to 662 U/ml and from 660 to 518 U/ml, respectively. No statistically significant correlation was observed between the serum level of IL-2R and the RF titre or percentage of C1q-binding activity, respectively. TNF was found within the normal range in all patients except one, who was characterized by active arthritis, high number of rheumatoid skin nodules and extremely high RF titre.(ABSTRACT TRUNCATED AT 250 WORDS)

Use of high-dose intravenous immunoglobulin in systemic lupus erythematosus: report of three cases.

Three patients with life-threatening manifestations of systemic lupus erythematosus (SLE), unresponsive to conventional high-dose corticosteroid and/or immunosuppressive therapy were treated with intravenous polyspecific IgG (IVIG). Following IVIG infusion, lupus encephalitis in the first patient quickly resolved and the impressive improvement of the clinical status was associated with a transient increase in C1q-binding activity. The daily infusion of IgG had to be suspended after three days in the second patient with encephalitis and nephritis, because the renal function rapidly deteriorated; subsequently, six plasma exchanges led to an almost complete recovery. Finally, leukocyte and platelet counts increased and remained within normal range following IgG therapy in the third patient having SLE-associated leuko- and thrombocytopenia. In all three patients a decrease in anti-DNA antibody levels and an increase in total complement hemolytic activity were detected after therapy.

Coronary heart disease and its risk factors in a group of 5,000 middle aged men in urban environment.

The results obtained at entry in the subjects included in a pilot study (Institute of Internal Medicine, Bucharest) for the detection and prevention of coronary heart disease and hypertension, are presented. These data are the prevalences of the risk factors of coronary heart disease (high serum cholesterol, hypertension, smoking, overweight, diabetes, nonspecific minor ECG signs, family history), as well as the prevalences of the various forms of coronary heart disease. The study of the frequency distribution of biologic parameters likely to become risk factors showed that in middle aged subjects the upper limit of the normal should be lowered from the 95th percentile to the 76th one.