Rapid screening of potential human bladder carcinogens: genotoxicity in meiosis repair deficient Drosophila melanogaster.

To find a quick screen of potential bladder carcinogens, a genotoxicity test in Drosophila melanogaster stocks containing DNA repair mutations was evaluated. Meiosis repair deficient male Drosophila melanogaster mei-9, mei-41, and the double mutant mei-9-41 were allowed to mate with attached -x females on media containing the test agent. Genotoxic agents produce DNA damage which accumulates and can be lethal in mei males, whereas the attached -x females are able to repair the damage and survive. Thus, the sex ratio of the progeny is a measure of genotoxicity which can be correlated with mutagenicity and carcinogenicity. In this study, tea, coffee, and saccharin were not genotoxic (p greater than 0.3). Dose dependent toxicity was observed in bracken fern (p less than 0.001). The known mutagen and bladder carcinogen, cyclophosphamide, was highly genotoxic (p less than .001). Drosophila genotoxicity not only permits rapid screening of mutagens, but may also have advantages over other systems in the screening of potential bladder carcinogens.

Long term protection in bladder cancer following intralesional immunotherapy.

Despite effective treatment of existing tumors, patients with bladder cancer remain at risk of developing new tumors. Effective immunotherapy may lower that risk. To test this hypothesis, mice that had survived transitional cell carcinoma (MBT2) transplantation with the aid of bacillus Calmette-Guerin immunotherapy were randomized and tested for long term protective immunity against bladder carcinoma. Fifty-one tumor-free mice that had survived tumor challenge 10 to 15 months previously were randomized into 3 groups to receive intradermal tumor .noculation and intraperitoneal levamisole, intralesional Tice strain bacillus Calmette-Guerin, or intralesional saline. Fifteen previously unchallenged animals also received tumor and intralesional saline. All 3 groups of survivors had less tumor growth (p less than 0.01) than nonsurviving controls. Even among survivors, additional bacillus Calmette-Guerin immunization, but not levamisole treatment, significantly inhibited tumor growth (p less than 0.01). A 2nd experiment compared 22 nonimmune mice, 21 mice preimmunized intravenously with 300 micrograms of bacillus Calmette-Guerin cell walls, and 18 mice that had survived MBT2 by 8 months after live bacillus Calmette-Guerin treatment. Nonimmune and survivor groups were randomly subdivided into saline or treatment groups. Cell wall-preimmunized mice were divided into matching groups according to footpad response to purified protein derivative. The cell-wall preimmunized and nonimmune mice received the immunostimulant P3+Re-glycolipid or the carrier solution alone. The group of survivors received either intralesional saline or live bacillus Calmette-Guerin. Both bacillus Calmette-Guerin and saline-treated groups had significantly less tumor growth (p less than 0.001) than nonsurviving controls. Animals treated with P3-Re-glycolipid (with or without preimmunization with cell wall) did not differ from nonsurviving control. Footpad response to purified protein derivative did not correlate with tumor growth in these mice. Our results suggest that intralesional bacillus Calmette-Guerin immunotherapy can afford long term protection from transplanted bladder cancer, and that live bacillus Calmette-Guerin is superior to levamisole and P3 + Re-glycolipid + bacillus Calmette-Guerin cell walls in the treatment of bladder cancer.

Survival of cadaveric renal allografts in Hispanic as compared with Caucasian recipients.

Evaluation of allograft survival rates revealed a significantly better overall graft survival in Hispanic (n = 66) as compared with Caucasian (n = 38) recipients of primary cadaveric renal transplants. There were no significant differences between the Hispanic and Caucasian cadaveric recipient groups in terms of patient survival, pretransplant transfusion status, immunosuppressive protocols, rejection therapy, mean age, or frequency of diabetes mellitus. Cadaveric donor ethnic origin (i.e., Caucasian or Hispanic) did not significantly alter graft survival rates in either recipient ethnic group. Although Caucasian patients with splenectomies had better cadaveric graft survival than Caucasian graft recipients without splenectomies (P = .02), splenectomy had no significant effect on the renal allograft survival rate in Hispanics. Other factors that were evaluated and found not to correlate significantly with cadaveric graft survival rates were donor recipient HLA matching (A, B, or DR), and panel reactivities of recipient pregraft serum samples. In contrast to the superior cadaveric renal allograft survival in Hispanic as compared with Caucasian recipients, 1-haplotype-matched or 2-haplotype-matched living-related renal allografts had comparable graft survival rates in Caucasian and Hispanic recipients. These results indicate that Hispanics without splenectomy enjoy a cadaveric renal allograft survival rate superior to nonsegregated populations (treated with conventional immunosuppression) reported elsewhere.

Immunotherapy of murine transitional cell carcinoma.

A series of 6 controlled experiments in C3H/He mice were performed to evaluate nonspecific immunotherapeutic regimens with a transplantable murine bladder tumor (MBT2). Immunotherapeutic agents studied included live Bacillus Calmette-Guerin (BCG) preparations in varying doses and strains (Tice, Pasteur, and Glaxo), Re mutant glycolipid (ReG) from Salmonella typhimurium, BCG cell wall skeletons (CWS), CWS plus B4 glycolipid fraction of ReG, and Keyhole-Limpet Hemocyanin (KLH). Animals received an intradermal MBT2 inoculation and were then randomized to treatment and control (saline treated) groups. Immunotherapy was administered intralesionally 1 day after tumor transplantation. Tumors were excised by amputation at a volume of 400 mm. and animals were later rechallenged with tumor inocula, again treated, and followed for tumor incidence growth rate and survival. No antitumor affect was observed with ReG, CWS or CWS plus B4. KLH immunotherapy did result in measurable antitumor effect. Consistent and statistically significant (p less than 0.01) antitumor responses as measured by prolonged survival and decreased growth rate were observed with Tice and Pasteur strains of BCG in doses ranging from 5 X 10(5) to 1 X 10(7) colony forming units per animal. Doses in excess of 10(7) units were found to decrease antitumor response. Glaxo strain BCG had no beneficial effect when used in the maximal dose (10(6) colony forming units) that could be administered. In animals immunized with intermediate doses of live Tice or Pasteur strain BCG in the study, effective long term immunity to transitional cell carcinoma was observed. Although many new immunotherapeutic agents have been advocated in other tumor models, to date we have found Tice and Pasteur strains of live BCG to be the most effective agents in the treatment of transitional cell carcinoma.

Keyhole-limpet haemacyanin and immune ribonucleic acid immunotherapy of murine transitional cell carcinoma.

Transitional cell carcinoma is known to be an immunogenic tumour. This immunogenicity has been the basis of a search for effective immunotherapeutic agents and for the evaluation in this study of two additional agents, keyhole-limpet haemacyanin (KLH) and immune ribonucleic acid (RNA) extract. The results in this animal model showed KLH to be a potent non-specific stimulant of the immune response which caused both a reduction in tumour growth and a prolongation of animal survival (p = 0.01). No anti-tumour effects were observed with either local or systemic RNA.

Levamisole immunotherapy of experimental transitional cell carcinoma.

Levamisole, in doses comparable to those under clinical investigation, was shown to significantly (P less than 0.02) delay the onset of transplanted transitional cell carcinoma of C3H mice. The growth of transplanted tumors was inhibited and animal survival prolonged with Levamisole treatment. Further progress in the immunotherapy of transitional cell carcinoma may be aided by such models.