Molecular biotherapy最新文献

Interferon-alpha and dacarbazine combination is a milestone in the treatment of metastatic malignant melanoma. Objective response rate ranged from 3% to 25%. Our phase II study included 34 patients; the overall response was 29.4%. Median time of survival of the responders was significantly longer than that of the nonresponders. Nine of the 34 patients had previously progressed on interleukin-2 (IL-2) and dacarbazine treatment, or had been withdrawn because of unacceptable toxicity. Two patients (22.2%) achieved partial responses. There seemed to be no cross-resistance between the two biologic response modifiers. Successful treatment of melanoma patients by interferon resulted in complete disappearance of all extracerebral lesions, but left the brain vulnerable to involvement by metastases, and was frequently a site of relapse. Brain irradiation is suggested by several investigators to prevent cerebral involvement. Ongoing protocols are an adjuvant treatment for high-risk patients and combination of interferon-alpha, IL-2, dacarbazine and cisplatinum for metastatic melanoma after failure of interferon-dacarbazine regimen.

An ultrasonicated lysate of Corynebacterium cutis (Ultracorn, Virbac, France) was administered to 10-day-old calves, 5-month-old calves, and pregnant dams kept under Egyptian environmental conditions. Ninety-five calves and 50 dams were used in the study. All animals were treated with 2 ml/100 kg body weight of killed C cutis. Its effects on body weight gain and on calf mortality and morbidity were recorded. The results obtained showed that treated calves had greater weight gains, reduced susceptibility to common viral pathogens, and lower mortality. When given simultaneously with rinderpest vaccine, an immunopotentiating or adjuvant effect was seen. Thus, treated calves had higher neutralizing antibody titers to rinderpest as compared with untreated calves. When administered to pregnant cows in the last month of pregnancy, the offspring of these animals had higher birth weight, better weight gain, and reduced morbidity.

Our 3-year clinical experience using recombinant interferon (rIFN) alpha-C in patients with metastatic renal cell carcinoma (RCC) is summarized. This type of IFN is a new subspecies of the IFN-alpha protein family. Its specific activity is 1-2 x 10(9) U/mg protein, the highest among IFN-alpha species presently available. Pharmacokinetic study indicated good bioavailability of the preparation from the intramuscular injection. A phase II study was performed to assess the response rate related to rIFN-alpha C at a low dosage. A dose of 3 x 10(6) U daily was administered, followed by 3 x 10(6) U/m2 every other day to avoid severe toxicity. Among 33 treated patients, a partial remission rate of 9.7% and stable disease rate of 25.8% were achieved. Side effects were usually mild and the treatment was well tolerated by the patients. However, mental deterioration and behavioral changes were observed in five patients with RCC treated by rIFN-alpha C and were related to neurotoxicity of IFN. The role of vinblastine in addition to IFN in the treatment of RCC was assessed in nine patients who had failed on IFN alone. No response was observed. It appeared that vinblastine had little if any effect in being added to IFN as second-line therapy. We conclude that rIFN-alpha C has moderate activity in the treatment of RCC. Familiarity with the possible toxicity of this agent will lead to more careful management of patients.

The success of adoptive immunotherapy using recombinant interleukin-2 (rIL-2) and lymphokine-activated killer (LAK) cells in several cancers has been hampered by severe toxicity associated with high doses of rIL-2. Methods that reduce the dosage of rIL-2 without loss of clinical efficacy are needed. In this study we determined the in vitro effect of a phytochemical immune modulator, Astragalus membranaceus (AM), and two fractions isolated by high-performance liquid chromatography on the cytotoxicity of rIL-2-generated LAK cells against a murine renal cell carcinoma. Our results indicated a 10-fold potentiation of rIL-2-generated LAK cell cytotoxicity manifested by tumor cell lysis of 88% in the group with 100 U/ml of rIL-2 plus AM versus 86% in the group with 1,000 U/ml of rIL-2 alone. Potentiation was obtained with the purified fractions as well. A significantly reduced number of LAK cells was required to achieve the tumor cytotoxicity after LAK cell generation with rIL-2 plus the phytochemicals as compared with rIL-2 alone. Our data indicate that AM is an effective immune modulator, capable of potentiating in vitro the antitumor activity of rIL-2-generated LAK cells.

The effect of recombinant interleukin 2 (rIL-2) on survival of mice with peritonitis and acute Staphylococcus aureus strain 5/2 infection was studied. rIL-2 was ineffective in the case of acute infection when administered simultaneously with LD95 dose of bacteria. The antibiotics (gentamycin or a combination of penicillin and streptomycin) administered in the same fashion cured 100% of animals. rIL-2 proved to be a potent healing agent in the two of three models of S aureus peritonitis. In this case animals received bacteria at days 0 and 2, 4, or 6. rIL-2 was injected at day 0 (group 1), days 0 and 2 (group 2), and days 0, 2, and 4 (group 3). Treatment with rIL-2 was ineffective in group 1; however, in groups 2 and 3 rIL-2 increased the survival up to 90% (in comparison with 30% in the untreated animals of group 2 and 64% in group 3). On the contrary, administration of antibiotics instead of rIL-2 in the group 3 decreased survival to 25%. The perspectives of rIL-2 use in the treatment of bacterial peritonitis, including purous ones, and the cases complicated by immunodepression, are discussed.

We report the occurrence of autoimmune hepatitis after treatment with interferon-alpha in a patient with Philadelphia chromosome-positive chronic myeloid leukemia. Cytogenetic and molecular genetic studies of the T lymphocytes in this patient demonstrated that the T lymphocytes were not part of the leukemic clone. The role of interferon in the production of autoimmune abnormalities is reviewed.

The effect of interleukin 3 (IL-3) on lymphokine-activated killer cell (LAK) generation in splenic lymphocytes was examined in patients with gastric cancer or idiopathic thrombocytopenic purpura (ITP). IL-3 alone did not induce any significant LAK activity from splenic lymphocytes. However, IL-3 addition to the culture with low-dose IL-2 significantly augmented the activity of LAK cells. Spleen cells precultured with IL-3 for 2 days and then added to IL-2 became more potent LAK cells than the spleen cells cultured with the same doses of IL-3 plus IL-2. Phenotypic analysis using flow cytometry demonstrated that IL-2 alone increased in cells expressing CD2+, -11+, and -16+ cells, whereas IL-3 plus IL-2 induced the expansion of CD3+ and CD8+ cells in addition to CD2+, -11+, and -16+ cells. These results suggest that IL-3 plus IL-2 phenotypically induces not only natural killer-like LAK cells (CD2+, -11+, and -16+) but T cell-like LAK cells (CD3+ and -8+). We are now investigating the characteristics of immature T cell populations in the spleen responsive to IL-3 using T-cell receptor antibody.

The survival of a host challenged by viral infection depends on many factors. Some are specific, such as antiviral T-cell and B-cell responses. Others are nonspecific, such as intrinsic cellular resistance, macrophage activation, and activation of humoral protective mechanisms (e.g., complement, coagulation, etc.). Cytokines are important mediators and regulators of both types of host response. Furthermore, orchestration of specific humoral and cellular immune responses requires the participation of many cytokines. Details of the complex and overlapping roles that cytokines play in specific immune responses is beyond the scope of this review. Instead, this review will focus on the nonspecific antiviral effects of cytokines.

Plasma lactoferrin content was measured before and after therapy with recombinant granulocyte-macrophage colony-stimulating factor in five patients with aplastic anaemia, six with myelodysplasia, and three with prolonged, severe, chemotherapy-induced neutropenia. Before therapy plasma lactoferrin content was uniformly low. However, patients with aplastic anemia and those with chemotherapy-induced neutropenia had a normal lactoferrin:neutrophil ratio. The low levels of plasma lactoferrin thus reflected the low granulocyte mass. On the other hand, patients with myelodysplasia also had reduced lactoferrin:neutrophil ratios, suggesting qualitative/quantitative abnormalities of neutrophil lactoferrin production. After treatment with granulocyte-macrophage colony-stimulating factor, plasma lactoferrin levels increased in patients with aplastic anemia and in those with chemotherapy-induced neutropenia who showed a neutrophil response to treatment. In these patients, the lactoferrin:neutrophil ratio became elevated, suggesting increased synthesis/release of lactoferrin from neutrophils. However, patients with myelodysplasia continued to show depressed lactoferrin:neutrophil ratios, even when there had been an increase in granulocyte count, suggesting persistent abnormalities of neutrophil lactoferrin production/release. The implications of these findings for treatment of neutropenic patients with granulocyte-macrophage colony-stimulating factors are discussed.