Abstract
DL-alpha-Difluoromethylornithine, a polyamine biosynthesis inhibitor, and bleomycin, a currently used antineoplastic agent, have each previously been shown to be curative for acute short-term infections of mice with Trypanosoma brucei brucei, an African trypanosome closely related to those that cause the human disease African sleeping sickness. These agents were tested singly and in combination in a previously described mouse model of sleeping sickness with demonstrable brain involvement. The original model is extended by using two additional strains of outbred mice and by demonstrating that melarsoprol, an arsenical and currently the only drug used for human African trypanosomiasis involving the brain, was also curative for these brain infections. Neither difluoromethylornithine nor bleomycin alone was curative for the brain infections; however, many combinations of the two drugs were found to be 100% curative with no evidence of immediate toxicity.
Full text
PDFSelected References
These references are in PubMed. This may not be the complete list of references from this article.
- Amole B. O., Clarkson A. B., Jr, Shear H. L. Pathogenesis of anemia in Trypanosoma brucei-infected mice. Infect Immun. 1982 Jun;36(3):1060–1068. doi: 10.1128/iai.36.3.1060-1068.1982. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Bacchi C. J. Content, synthesis, and function of polyamines in trypanosomatids: relationship to chemotherapy. J Protozool. 1981 Feb;28(1):20–27. doi: 10.1111/j.1550-7408.1981.tb02798.x. [DOI] [PubMed] [Google Scholar]
- Bacchi C. J., Garofalo J., Mockenhaupt D., McCann P. P., Diekema K. A., Pegg A. E., Nathan H. C., Mullaney E. A., Chunosoff L., Sjoerdsma A. In vivo effects of alpha-DL-difluoromethylornithine on the metabolism and morphology of Trypanosoma brucei brucei. Mol Biochem Parasitol. 1983 Mar;7(3):209–225. doi: 10.1016/0166-6851(83)90022-1. [DOI] [PubMed] [Google Scholar]
- Bacchi C. J., Nathan H. C., Hutner S. H., McCann P. P., Sjoerdsma A. Novel combination chemotherapy of experimental trypanosomiasis by using bleomycin and DL-alpha-difluoromethylornithine; reversal by polyamines. Biochem Pharmacol. 1982 Sep 1;31(17):2833–2836. doi: 10.1016/0006-2952(82)90144-7. [DOI] [PubMed] [Google Scholar]
- Bacchi C. J., Nathan H. C., Hutner S. H., McCann P. P., Sjoerdsma A. Polyamine metabolism: a potential therapeutic target in trypanosomes. Science. 1980 Oct 17;210(4467):332–334. doi: 10.1126/science.6775372. [DOI] [PubMed] [Google Scholar]
- Case D. C., Jr, Young C. W., Nisce L., Lee B. J., 3rd, Clarkson B. D. Eight-drug combination chemotherapy (MOPP and ABDV) and local radiotherapy for advanced Hodgkin's Disease. Cancer Treat Rep. 1976 Sep;60(9):1217–1223. [PubMed] [Google Scholar]
- Cohen S. S. Comparative biochemistry and drug design for infectious disease. Science. 1979 Sep 7;205(4410):964–971. doi: 10.1126/science.382357. [DOI] [PubMed] [Google Scholar]
- Cohen S. S. The polyamines as a growth industry. Fed Proc. 1982 Dec;41(14):3061–3064. [PubMed] [Google Scholar]
- Giri S. N., Hyde D. M., Schwartz L. W., Younker W. R. The effect of alpha-difluoromethylornithine on the development of bleomycin-induced pulmonary fibrosis in hamsters. Am J Pathol. 1982 Oct;109(1):115–122. [PMC free article] [PubMed] [Google Scholar]
- Jennings F. W., Whitelaw D. D., Holmes P. H., Chizyuka H. G., Urquhart G. M. The brain as a source of relapsing Trypanosoma brucei infection in mice after chemotherapy. Int J Parasitol. 1979 Aug;9(4):381–384. doi: 10.1016/0020-7519(79)90089-4. [DOI] [PubMed] [Google Scholar]
- Jennings F. W., Whitelaw D. D., Urquhart G. M. The relationship between duration of infection with Trypanosoma brucei in mice and the efficacy of chemotherapy. Parasitology. 1977 Oct;75(2):143–153. doi: 10.1017/s0031182000062284. [DOI] [PubMed] [Google Scholar]
- Jänne J., Alhonen-Hongisto L., Seppänen P., Siimes M. Use of polyamine antimetabolites in experimental tumours and in human leukemia. Med Biol. 1981 Dec;59(5-6):448–457. [PubMed] [Google Scholar]
- Karbe E., Böttger M., McCann P. P., Sjoerdsma A., Freitas E. K. Curative effect of alpha-difluoromethylornithine on fatal Trypanosoma congolense infection in mice. Tropenmed Parasitol. 1982 Sep;33(3):161–162. [PubMed] [Google Scholar]
- McCann P. P., Bacchi C. J., Clarkson A. B., Jr, Seed J. R., Nathan H. C., Amole B. O., Hutner S. H., Sjoerdsma A. Further studies on difluoromethylornithine in African trypanosomes. Med Biol. 1981 Dec;59(5-6):434–440. [PubMed] [Google Scholar]
- Nathan H. C., Bacchi C. J., Hutner S. H., Rescigno D., McCann P. P., Sjoerdsma A. Antagonism by polyamines of the curative effects of alpha-difluoromethylornithine in Trypanosoma brucei brucei infections. Biochem Pharmacol. 1981 Nov 1;30(21):3010–3013. doi: 10.1016/0006-2952(81)90270-7. [DOI] [PubMed] [Google Scholar]
- Nathan H. C., Bacchi C. J., Sakai T. T., Rescigno D., Stumpf D., Hutner S. H. Bleomycin-induced life prolongation of mice infected with Trypanosoma brucei brucei EATRO 110. Trans R Soc Trop Med Hyg. 1981;75(3):394–398. doi: 10.1016/0035-9203(81)90101-2. [DOI] [PubMed] [Google Scholar]
- Pegg A. E., McCann P. P. Polyamine metabolism and function. Am J Physiol. 1982 Nov;243(5):C212–C221. doi: 10.1152/ajpcell.1982.243.5.C212. [DOI] [PubMed] [Google Scholar]
- Sjoerdsma A. Suicide enzyme inhibitors as potential drugs. Clin Pharmacol Ther. 1981 Jul;30(1):3–22. doi: 10.1038/clpt.1981.121. [DOI] [PubMed] [Google Scholar]
- Takeuchi K. A clinical trial of intravenous bleomycin in the treatment of brain tumors. Int J Clin Pharmacol Biopharm. 1975 Dec;12(4):419–426. [PubMed] [Google Scholar]
- Tofilon P. J., Oredsson S. M., Deen D. F., Marton L. J. Polyamine depletion influences drug-induced chromosomal damage. Science. 1982 Sep 10;217(4564):1044–1046. doi: 10.1126/science.6810463. [DOI] [PubMed] [Google Scholar]
- Vugrin D., Cvitkovic E., Whitmore W. F., Jr, Cheng E., Golbey R. B. VAB-4 combination chemotherapy in the treatment of metastatic testis tumors. Cancer. 1981 Mar 1;47(5):833–839. doi: 10.1002/1097-0142(19810301)47:5<833::aid-cncr2820470502>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
- Williamson J. Chemotherapy of African trypanosomiasis. Trop Dis Bull. 1976 Jul;73(7):531–542. [PubMed] [Google Scholar]