Effects of cyclosporin A on cell fusion in a monkey kidney cell line persistently infected with measles virus.

The authors studied the effects of immunosuppressive peptide cyclosporin A (CsA) on cell fusion efficiency in cells persistently infected with measles virus (448-PI-Vero cells). Treatment of 448-PI-Vero cells with 5 microM CsA enhanced the infusion. In addition, the expression of measles virus antigen on cell surface was increased by treatment with CsA. The addition of phenothiazine, an anti-calmodulin drug, enhanced the fusion of 448-PI-Vero cells in the presence of CsA, although treatment with phenothiazine alone did not affect polykaryocyte formation. The enhancement of fusion efficiency in 448-PI-Vero cells by CsA was suppressed by oligopeptide Z-D-Phe-Phe-Gly, a synthetic oligopeptide that inhibits fusion induced by measles virus. Since the cell content of major virus-specific polypeptides, such as hemagglutinin, nucleoprotein or matrix protein is the same as in untreated controls, this fusion enhancement may be related to transport and accumulation of measles virus glycoproteins.

[Management of mycobacteriosis in general hospital without isolation ward for tuberculosis patients. 3. Current status of tuberculosis patient care in university hospitals and general hospitals in Japan].

A recent epidemiological survey has revealed that the incidence of Mycobacterium tuberculosis (TB) patients in Japan has just increased again after four decades of decline. In fact, recently there have been numerous reports of TB outbreaks in health-care facilities. Although our medical school hospital does not have TB isolation rooms, we have to take care of more than a few TB patients, most of whom have been transferred from primary care clinics. Although, some of these TB patients have highly infectious (sputum smear positive), most of them have not been diagnosed as having highly infectious TB, and therefore, some of their patients ultimately have to be retransferred to a TB hospital. This indicates that most physicians in primary care clinics have little knowledge about TB. This may be partly because of lack of training regarding TB during their medical student days and residencies. To elucidate current TB patient care status in university hospitals in Japan, a survey of physicians working in such hospitals was conducted from September 1997 to January 1998. The survey (questionnaire) revealed that the majority (76%) of these hospitals do not have TB isolation rooms. However, these hospitals have to take care of TB patients in their outpatient clinics and sometimes on their wards because the patients have serious complications that can not be treated in ordinary TB hospitals. The survey also showed that for this reason and from an educational point of view, the majority of the physicians (90%) working in these hospitals thought that university hospitals should have isolation rooms for such patients. Another questionnaire revealed that few physicians and nurses in university hospitals have sufficient experiences in taking care of TB patients. This situation may have been responsible for producing physicians with little knowledge about TB. Recent scientific advances have made it possible to construct TB isolation rooms in ordinary wards by means of separate ventilation systems. Although combatting TB requires a variety of strategies, appropriate education for both medical students and residents using isolation rooms in university hospitals may be an effective means of preventing spread of TB, and this approach may also increase awareness concerning the prevention of TB outbreaks in hospitals and health-care facilities.

Targeted gene transfer for adenocarcinoma using a combination of tumor-specific antibody and tissue-specific promoter.

We have developed a highly specific gene transfer method for adenocarcinoma using a monoclonal antibody against tumor-specific antigen coupled with a plasmid containing the carcinoembryonic antigen (CEA)-specific promoter. The chimeric CEA promoter (CC promoter), which contained an enhancer from the immediate early gene of cytomegalovirus and the CEA promoter, achieved 4- to 5-fold higher transgene expression in CEA-producing cells than the original CEA promoter while maintaining CEA specificity. Furthermore, a complex of a monoclonal antibody against Lewis Y antigen (LYA), the CC promoter-containing plasmid and cationic liposomes (DOTAP) achieved specific gene expression in CEA-producing and LYA-positive adenocarcinoma cell lines that was 200-fold more efficient than in CEA-non-producing and LYA-negative cell lines during a short in vitro incubation. This strategy may be applicable for clinical gene therapy.

Cytokines as an adjuvant to tumor vaccines: efficacy of local methods of delivery.

BACKGROUND: We examined alternative methods of delivering cytokines as an adjunct for priming lymph node (LN) cells draining sites of vaccine inoculation for the purpose of generating immune cells for adoptive immunotherapy. METHODS: Using syngeneic murine tumors we examined the ability of IL-2, IL-4, or GM-CSF delivered locally to a site of tumor inoculum to induce antitumor reactive draining LN cells. Mice were inoculated subcutaneously with tumor cells transduced to secrete cytokine; tumor cells admixed with fibroblasts transduced to secrete cytokine; or intralesional inoculation of cytokine in established tumor to induce sensitized LN cells capable of mediating tumor regression in adoptive transfer. RESULTS: Both IL-4 and GM-CSF cytokines were effective in enhancing the antitumor reactivity of vaccine-primed LN cells compared to IL-2, which was ineffective. The local delivery of GM-CSF by autocrine or paracrine secretion of genetically engineered cells, as well as direct intratumoral delivery was capable of upregulating LN sensitization compared to systemic administration, which did not. CONCLUSIONS: The local delivery of GM-CSF as an adjuvant for tumor vaccination can be accomplished by various methods, including direct injection, which avoids the need for gene transfer.

[A randomized phase II study of (2''R)-4'-0-tetrahydropyranyladriamycin and adriamycin in combination with vincristine and ACNU in small cell lung cancer--THP-ADM, VCR, ACNU vs ADM, VCR, ACNU].

Between April 1984 and March 1988, a comparative randomized phase II study was performed to compare the effects of (2''R)-4'-0-Tetrahydropyranyl-adriamycin (THP) and adriamycin in combination with vincristine (VCR) and ACNU in 60 previously untreated and evaluable patients with small cell lung cancer (SCLC). Arm AVA was constituted by adriamycin, VCR and ACNU, and arm TAVA by THP, VCR, ACNU. Of the 30 patients treated with AVA, there were 20 partial responses, 7 with no change and 3 with progressive disease, for an overall response rate of 66.7%. On the other hand, of the 30 patients on TAVA, one complete response and 22 partial responses were observed, for an overall response rate of 76.7% Median survival time of AVA was 10.0 M, that, of TAVA was 9.3 M. But significant differences between the two arms was not found. During induction therapy, leukopenia was the main side effect. Over WHO Grade 3 leukopenia was seen in 53.3% of patients on AVA and 70.0% of those on TAVA. Moderate hair loss (Grade 2) was significantly less frequent with TAVA than AVA. In conclusion, the results indicated that THP is active in SCLC with the same level of adriamycin, and has less toxicity. THP is a suitable drug as a first line combination chemotherapy for SCLC.

[A comparative randomized phase II study of CDDP, CDDP-carboquone (CQ) and CDDP-etoposide as second-line chemotherapy in small cell lung cancer (SCLC)].

51 SCLC patients who had received prior chemotherapies and had measurable lesions were randomized to CDDP, CDDP-CQ, and CDDP-etoposide treatment group. Prior chemotherapies of 49 complete cases were AVA (ADM, VCR, ACNU; 16 cases), TAVA (THP-ADM, VCR, ACNU; 17 cases), CAV (CPA, ADM, VCR; 4 cases) and others. The median period of 49 cases from prior chemotherapy to this chemotherapy was 4 weeks. In the CDDP alone group, CDDP was given at a dose of 80 approximately 100 mg/m2/4-5 weeks on Day 1, and in CDDP-CQ treatment group, patients were given the same dose of CDDP and CQ 6 mg/body on Day 1, 2. In CDDP-etoposide treatment group, the same doses of CDDP and etoposide 60 mg/m2 Day 1-5 (Total 300 mg/m2) were given. Response rate of the CDDP alone group was 6.7% (PR 1/total 15), that of CDDP-CQ group was 6.3% (PR 1/total 16), and in CDDP-etoposide group it was 16.7% (PR 3/total 18). In CDDP-CQ treatment, the main side effect was strong hematotoxicity (WBC; Grade 3, 5 patients, Grade 4, 2 Pl: Grade 3, 5 Grade 4, 3), and main hematotoxicity of CDDP-etoposide was leukopenia (W BC; Grade 3, 4 patients, Grade 4, 2 Pl; Grade 4, 1). In these patients, it was thought that CDDP was not useful in second chemotherapy, as not only CDDP alone but also the combination with CQ or etoposide.