Molecular biotherapy最新文献

It has been ascertained that one of several possible reasons for negligible interferon activity in solid tumors, namely, hepatic metastases induced in rats after intraportal injection of Walker carcinoma 256 cells, is the significantly lower levels of interferon in the interstitial fluid of metastases in comparison to normal liver and plasma.

Colostrum-deprived neonate piglets challenged with rotavirus and 3-week-old newly weaned piglets naturally exposed to rotavirus were treated with low doses of natural human interferon alpha (nHuIFN alpha) administered into the oral cavity or included in the liquid diet. The colostrum-deprived piglets given the highest dosage of nHuIFN alpha (50 IU/kg body weight) had lower viral excretion scores at 3 (p less than 0.11) and 4 days (p less than 0.001) after virus inoculation. Average group weights and weight gains were consistently greater for all nHuIFN alpha-treated neonate groups; however, these differences were not significant. Mortality rates were lower in neonates for the three highest nHuIFN alpha treatment groups (20%, 30%, and 20%) than in the lowest treatment group and controls (60% and 45%, respectively). Three-week-old weanling piglets did not have significant differences in the total average diarrhea or rotavirus excretion scores. After 10 days, the group receiving the highest dosage of nHuIFN alpha had significantly greater average weight gain than the control group (p less than 0.05). There was a significant (p less than 0.01) dose-dependent effect between the logarithm10 of the nHuIFN alpha dosage and weight gain in weanling piglets. There were no death losses in the 3-week-old weanling piglets from natural rotavirus exposure.

Assuming that the attributes of the mitogenic-leukoaggglutinating (L4) isolectin of phytohemagglutinin as a proposed ideal biologic response modifier can be confirmed, it could prove to be a highly versatile agent with broad therapeutic potential for several areas of management including cancer and cancer surgery adjuvant, critical infections (including that with the human immunodeficiency viruses), vaccine adjuvant, allograft transplantations, aplastic anemias, and extensive burns. The isolectin is predictably more likely to be effective as an adjuvant or adjunctive agent than as an induction agent. Initial evaluation in dogs would serve the double purpose of establishing a presumptive key role in veterinary medicine and expediting the development of its use in humans.

The effect of mouse recombinant interferon-gamma (IFN-gamma) on murine lymphokine-activated killer (LAK) cell activity was investigated using a natural killer-resistant, LAK-sensitive, spontaneously developed, weakly immunogenic, syngeneic murine mammary adenocarcinoma, a tumor model mimicking that of human disease. When all of the splenocytes prepared from tumor-bearing mice were cultured with recombinant interleukin-2 (IL-2) and IFN-gamma, LAK cell activity was suppressed in an IFN-gamma dose-dependent manner. An increase in the prostaglandin E2 (PGE2) content in the corresponding culture media was detected, as was IFN-gamma dose dependent. The suppression of generation of LAK cell activity by IFN-gamma was abrogated, accompanied by the elimination of the increase in PGE2 content, when plastic dish and nylon wool-treated nonadherent macrophage-depleted splenocytes were used. These results indicated that IL-2-induced LAK cell activity generated from the splenocytes of tumor-bearing mice was suppressed by IFN-gamma, and that PGE2 secreted from the macrophages of the splenocyte cultures served as the mediator in this IFN-gamma dose-dependent suppression of IL-2-induced LAK cell activity.

alpha-Interferon, 3 x 10(6) U/m2 every other day, and dacarbazine, up to 800 mg/m2 every 3 weeks, were given to nine patients with metastatic malignant melanoma who had progressed on a combination of interleukin-2 and dacarbazine. Partial response was documented in two patients for 9 and 4 months. Responsive sites were the lungs, lymph nodes, liver, and skin. Failure to respond to one biologic response modifier does not predict the response to another modifier.

Two patients with chronic major aphthous stomatitis of at least 3 years duration were treated with single daily oral doses (1,200 IU) of interferon alfa-2 alpha (HuIFN alpha). Both patients responded with complete remission of aphthae within 6 weeks. One patient had no recurrence of the disease during a 6-month observation period. The second patient had a recurrent aphtha approximately 4 weeks after the initial lesion resolved; however, the recurrent lesion was less severe than the patient had historically experienced. Retreatment of the recurrent lesion with HuIFN alpha resulted in complete remission within 1 week, and there were no further recurrences during the 6-month observational period.

A monoclonal antibody, 1C1, developed using a trans-R,R-1,2-diamminocyclohexane (DACH) modified platinum analog (DACH-Pt-SO4) complexed with DNA was shown, using the enzyme-linked immunosorbent assay (ELISA), to have the ability to bind to both free drug DACH-Pt-SO4 and to the drug-DNA complex. Using competitive ELISA, 1C1 was found to recognize non-DACH-containing platinum compounds, such as cis-dichlorodiammine platinum (II) (CDDP). 1C1 exhibited strong binding to slot-blotted, DACH-Pt-SO4-treated DNA and moderate binding to the CDDP-DNA complex, but was unable to detect DACH containing methyliminodiacetato-trans-R,R-1,2-diamminocyclohexane platinum (II) (MIDP)-modified DNA. Immunocytochemical staining studies using 1C1 antibody on CDDP-treated BRO melanoma cells showed preferential staining of the cytosol compared with the nucleus. Although the extent of staining was dose dependent, a heterogeneous staining pattern was observed. Multicellular spheroids of MDA886LN squamous carcinoma cells treated with CDDP showed intense staining on the growing periphery compared with weak but homogeneous staining within the spheroid. Cell cycle-dependent uptake of CDDP in synchronized BRO cells may partly explain the observed heterogeneity of platinum distribution.

The effects of chemotherapy or local irradiation on lymphokine-activated killer (LAK) cell accumulation into tumor sites were investigated. Lymphokine-activated killer cells labeled with 111In-oxine were injected into the caudal vein of C57BL/6 mice that had been previously transplanted with 3LL cancer. An adoptive transfer of LAK cells was carried out 4 days after treatments. Twenty-four hours after the transfer, tumor tissues were excised, and the accumulation of labeled LAK cells in the tumor was measured. In two different experiments, LAK cell accumulation in tumor in the nontreated group was 2.15% and 1.58% of the administered dose per gram of tissue. The accumulation in the groups of mice treated with cyclophosphamide, nimustine hydrochloride, or Adriamycin increased fourfold (7.38% dose/g, 6.61% dose/g), threefold (6.47% dose/g) and twofold (4.46% dose/g), respectively, as compared with the nontreated group. These agents induced significant tumor regression. In the group treated with bleomycin, which showed no significant effect on tumor growth, LAK cell accumulation in tumor remained unaltered (1.57% dose/g). However, the group treated with local irradiation, which induced significant tumor reduction, showed no increase in LAK cell accumulation into tumors. These results suggest that some antitumor drugs enhance LAK cell accumulation into tumor sites and that this increase is due to tumor modification by antitumor drugs.

A review of reproductive biology and oncologic immunology reveals striking similarities between the tolerance of neoantigen as demonstrated in pregnancy and cancer. The author discusses the phylogeny of sexual reproduction and the oncologic condition, and suggests that an evolved mechanism of acquired tolerance to HLA-incompatible tissue necessitated by sexual reproduction consequently provides a mechanism for the tolerance of cancer.