Biotechnology therapeutics最新文献

Administration of rHuIFN-alpha A/D and rMuIFN-gamma as single agents to tumor-bearing mice resulted in a dose-related antitumor effect in each of the six models studied. When the IFNs were given in combination, the effects varied between the tumor systems. No increase in efficacy was seen in mice bearing B16-F10 melanoma or M5076 reticulum cell sarcoma while additive antitumor activity was shown in the KA31 fibrosarcoma and P388 leukemia systems. Mice inoculated with L1210 lymphoma or colon 38 carcinoma, however, revealed enhanced efficacy which was greater than additive. The data also reveal that combination of IFNs alpha and gamma administered to normal and tumor-bearing mice resulted in toxicity which was not predicted by the appropriate doses of the single agents. These studies suggest that combination of IFNs alpha and gamma may provide greater therapeutic utility than the single agents and underscore the need for additional, carefully designed preclinical and clinical efforts.

Recombinant human interleukin-3 (rhuIL-3) was assessed for its effects on the growth of normal human hematopoietic bone marrow nucleated cells, and on granulocyte-macrophage (CFU-GM) and erythroid (BFU-E) progenitor cells in a liquid culture system which allows for the prolonged growth of these cells in vitro. RhuIL-3, at concentrations of 100 and 500 units/mL, significantly enhanced the numbers of nucleated cells, as well as the numbers of supernatant and adherent CFU-GM and BFU-E growing in tissue culture flasks or dishes over a period of 4 to 6 weeks. The results demonstrated the rhuIL-3 has a stimulating effect on the growth of human marrow cells in prolonged culture. This information is consistent with the effects of rhuIL-3 in short-term marrow colony assays in vitro and with the in vivo actions of recombinant murine IL-3 in mice, and may be of relevance to clinical trials that will be assessing the hematopoietic effects of rhuIL-3 in humans.

Two models of wound repair compared the effect of defined, recombinant growth factors on the rate of wound repair in both normal and streptozotocin-induced diabetic rats: subcutaneous implantation of polyvinyl alcohol sponges and incisional wounding. Transverse incisional wounds were made on the dorsal surface of rats and closed with steel sutures. Three days postwounding the rats received a single injection of either transforming growth factor-beta or vehicle alone directly into the wound site. Animals were sacrificed 7, 14, and 21 days postwounding, and fresh and formalin-fixed wound tensile strength were measured. Diabetic rats had expected defects in wound repair, including decreased granulation tissue and reduced amounts of collagen, protein, and DNA. Fresh tensile strength of the diabetic incisions was 53% of normal on Day 7 (p < or = .01) and 29% of normal on Day 21. Fixed tensile strength was 41% of normal on Day 7 (p < or = .01) and fell to 78% of normal by Day 21 (p < or = .01), suggesting that collagen concentrations of diabetic wounds increased towards normal but did not undergo maturation. TGF beta produced a moderate increase in tensile strength of fresh and fixed wounds of diabetic rats, but not to the levels of wounds in untreated normal rats. Sponges fill with granulation tissue, their reproducible rate of organization being measured by histological and biochemical methods. A single injection into sponges 3 days postimplantation of basic fibroblast growth factor, transforming growth factor-beta, or vehicle only, was evaluated at 7 and 9 days postimplantation. In the sponge model, bFGF and TGF beta were each able to induce significant increases in the accumulation of granulation tissue in both diabetic and normal rats. TGF beta increased the collagen content of sponges by 136% in sponges from diabetic animals (p < or = .001), thereby raising the collagen content to that of normal control wounds, while stimulating a 49% (p < or = .02) increase in sponges from normal animals on Day 9. By contrast, the response to bFGF was predominantly an increase in the protein and DNA content of the sponges. These results emphasize the differential effects of the two cytokines in accelerating healing under conditions of defective wound repair.

A clinical trial was conducted to determine the tolerance and toxicity of recombinant tumor necrosis factor (rTNF) and recombinant interferon gamma (rIFN-gamma) when administered concurrently by continuous intravenous infusion to 11 patients with the AIDS-related complex (ARC). In addition, HIV culture, p24 antigen levels, and CD4 positive lymphocytes were monitored to obtain preliminary evidence of antiviral and immunologic effects. Two 5-day treatment cycles were separated by a 9-day washout period. Two patients were entered at each dosage level and each patient received the two 5-day treatment cycles at two sequential dose levels ranging from 1 to 25 micrograms/m2. Two patients did not complete their second treatment cycle--one due to the development of a rash, the second due to central venous catheter discomfort. The occurrence of phlebitis with peripheral vein administration of these agents necessitated administration via central venous catheter. With the exception of a single patient who developed severe headache at the 25 micrograms/m2 dose, severe clinical toxicities were not observed. Fever, chills, headache, and myalgias were the most significant clinical toxicities observed and all were dose dependent. The percentage fall in total granulocytes was dose dependent and ranged from 17% at the 1 microgram/mm2 dose to 48% at both the 15 and 25 micrograms/mm2 dose levels. The mean nadir granulocyte count was 1694/mm3. No significant renal or hepatic toxicity was observed. Of 22 treatment cycles the CD4 cell number was increased in 11, unchanged in 7, and decreased in 4. The mean CD4 cell number did not change significantly (176 +/- 143/mm3 pretherapy versus 279 +/- 305/mm3 posttherapy).(ABSTRACT TRUNCATED AT 250 WORDS)