Tumor-burdened Mice Research Articles

Radiation induced oxidative stress: II studies in liver as a distant organ of tumor bearing mice.

Since the radiation dose tolerance of normal tissues/organs away from the site of tumor influences the success of radiation therapy of cancer, and antioxidant status is likely to be one of the factors to determine the tolerance; the radioresponse of antioxidant enzymes has been examined in the liver as a representative distant organ in the tumor-bearing mice. Swiss albino male mice (7-8 weeks old) with Ehrlich solid tumor in the thigh pad were irradiated with different doses of gamma-radiation (0-9 Gy) at a dose rate of 0.0153 Gy/s and the specific activities of enzymes involved in the free radical metabolism were determined in the liver. Except GST, the activities of SOD, DTD and Gly I as well as the GSH content were found to be higher in the liver of tumor-bearing mice compared to the non-tumor bearing mice. The catalase activity progressively decreased with dose in both the groups of mice. However, the activity was relatively higher in the liver of tumor- bearing mice than the control. Thus, the radioresponse of antioxidant enzymes seemed to be significantly different in the liver of tumor-burdened mice compared to controls. The enhanced activities might be due to relatively more damage caused by radiation. The higher levels of NO* and peroxidative damage in the liver of tumor-bearing mice probably suggest this possibility. These findings of the present work might have some serious implications as the increased radiation-damage of the distant normal organs (due to tumor burden) is likely to adversely affect the therapeutic gain.

Cure of Multidrug-Resistant Human B-Cell Lymphoma Xenografts by Combinations of Anti-B4-Blocked Ricin and Chemotherapeutic Drugs

The CD-19-directed immunotoxin anti-B4-blocked ricin (anti-B4-bR) is currently in clinical trials for the treatment of B-cell malignancies. To explore the potential of using anti-B4-bR with chemotherapy protocols we tested the in vivo efficacy of the immunotoxin in combination with two multi-drug chemotherapeutic regimens in severe combined immunodeficient (SCID) mice bearing disseminated tumors of the multidrug-resistant human B-cell lymphoma Namalwa/mdr-1. In cytotoxicity studies in vitro, combinations of the immunotoxin with cisplatin produced supra-additive killing effects on both Namalwa and Namalwa/mdr-1 cells, whereas anti-B4-bR combined with 4-hydroperoxy-cyclophosphamide caused additive killing of both cell lines. In vivo cyclophosphamide, cisplatin, vincristine, doxorubicin, and etoposide as single agents, were effective in prolonging the survival of SCID mice burdened with the Namalwa tumor, whereas only cyclophosphamide and cisplatin were effective on Namalwa/mdr-1 tumors. Treatment of Namalwa/mdr-1-bearing mice with anti-B4-bR alone or with the drug combination CHOE (consisting of cyclophosphamide, vincristine, doxorubicin, and etoposide) alone increased the lifespan of the tumor-burdened mice by 58% and 73%, respectively. However, treatment with five daily bolus intravenous injections of anti-B4-bR followed by CHOE increased the lifespan by 173%, and 20% of the mice were cured. The drug combination CCE (cyclophosphamide, cisplatin, and etoposide) alone could increase the lifespan of the Namalwa/mdr-1 tumor-burdened mice by 129% compared with untreated controls. Combination therapy with anti-B4-bR and CCE produced long-term cures in 50% of the tumor-burdened mice. These results suggest that anti-B4-bR in combination with current multidrug regimens may constitute a highly efficacious modality for the treatment of drug-resistant B-cell malignancies.

Characteristics of Complement Receptor-Bearing Cells in the Spleens of Tumor-Bearing Mice

In the course of mammary tumor development, a population of nylon nonadherent cells with CR appears in the spleens of tumor-bearing mice although none are ever detected in normal mice. These cells apparently arise in response to immunologic stimulation. In a series of studies we have further characterized subsets of T cells (CR+ and CR-) with regard to their responses to mitogens in the lymphocyte transformation assay. Nylon column nonadherent cells from the spleens of tumor-bearing mice were rosetted in a complement receptor assay using EAC rosetting, and CR+ cells were separated from CR- by centrifugation in a discontinuous Ficoll gradient. CR+ T cells responded strongly to PHA and Con A and in addition responded to LPS, an activity not usually associated with conventional T cells. In contrast, CR- T cells from tumor-burdened mice responded to PHA but failed to respond to Con A or LPS.