Abstract
Nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) inhibits the transport of nucleosides, including tubercidin, in mammalian systems but not in Schistosoma mansoni. Administration of NBMPR-P with high doses of tubercidin (lethal doses if injected alone) by intraperitoneal injection into S. mansoni-infected mice was highly toxic to the parasite but not to the host. Combination therapy resulted in a striking decrease in the number and copulation of worms. The few worms that could be found were so stunted that it was difficult to identify their sex. Mice receiving the combination of tubercidin plus NBMPR-P appeared healthy and had normal-sized livers and spleens. Combination therapy also caused a drastic decrease in the number of eggs in the liver (from 32,500 to 1,800 eggs per liver) and in the intestine (from 1,295 to 2 eggs per cm2). All eggs found were dead, indicating the termination of oviposition. Very few granulomas were detected in livers of treated animals. Sections of these livers showed lesions containing dead worms and what appeared to be a process of regeneration of normal tissue around old granulomas. Thus, combination therapy reduced the number and the progress of the primary pathological lesions associated with schistosomiasis. These results demonstrate that through combination therapy, highly selective toxicity against a parasite can be achieved. The effectiveness, simplicity, and practicality of host protection afforded by this method may yield a promising chemotherapeutic approach for the treatment of schistosomiasis and other parasitic diseases.
Full text
PDF
Images in this article
Selected References
These references are in PubMed. This may not be the complete list of references from this article.
- CLEGG J. A. IN VITRO CULTIVATION OF SCHISTOSOMA MANSONI. Exp Parasitol. 1965 Apr;16:133–147. doi: 10.1016/0014-4894(65)90037-8. [DOI] [PubMed] [Google Scholar]
- Cheever A. W. Conditions affecting the accuracy of potassium hydroxide digestion techniques for counting Schistosoma mansoni eggs in tissues. Bull World Health Organ. 1968;39(2):328–331. [PMC free article] [PubMed] [Google Scholar]
- Jaffe J. J., Meymarian E., Doremus H. M. Antischistosomal action of tubercidin administered after absorption into red cells. Nature. 1971 Apr 9;230(5293):408–409. doi: 10.1038/230408a0. [DOI] [PubMed] [Google Scholar]
- Jaffe J. J. Nucleoside analogs as antiparasitic agents. Ann N Y Acad Sci. 1975 Aug 8;255:306–316. doi: 10.1111/j.1749-6632.1975.tb29238.x. [DOI] [PubMed] [Google Scholar]
- Knopf P. M., Nutman T. B., Reasoner J. A. Schistosoma mansoni: resistance to reinfection in the rat. Exp Parasitol. 1977 Feb;41(1):74–82. doi: 10.1016/0014-4894(77)90131-x. [DOI] [PubMed] [Google Scholar]
- Kolassa N., Jakobs E. S., Buzzell G. R., Paterson A. R. Manipulation of toxicity and tissue distribution of tubercidin in mice by nitrobenzylthioinosine 5'-monophosphate. Biochem Pharmacol. 1982 May 15;31(10):1863–1874. doi: 10.1016/0006-2952(82)90489-0. [DOI] [PubMed] [Google Scholar]
- LEE C. L., LEWERT R. M. The maintenance of Schistosoma mansoni in the laboratory. J Infect Dis. 1956 Jul-Aug;99(1):15–20. doi: 10.1093/infdis/99.1.15. [DOI] [PubMed] [Google Scholar]
- Lynch T. P., Jakobs E. S., Paran J. H., Paterson A. R. Treatment of mouse neoplasms with high doses of tubercidin. Cancer Res. 1981 Aug;41(8):3200–3204. [PubMed] [Google Scholar]
- Ogbunude P. O., Ikediobi C. O. Effect of nitrobenzylthioinosinate on the toxicity of tubercidin and ethidium against Trypanosoma gambiense. Acta Trop. 1982 Sep;39(3):219–224. [PubMed] [Google Scholar]
- PELLEGRINO J., OLIVEIRA C. A., FARIA J., CUNHA A. S. New approach to the screening of drugs in experimental schistosomiasis mansoni in mice. Am J Trop Med Hyg. 1962 Mar;11:201–215. doi: 10.4269/ajtmh.1962.11.201. [DOI] [PubMed] [Google Scholar]
- Paterson A. R., Kolassa N., Cass C. E. Transport of nucleoside drugs in animal cells. Pharmacol Ther. 1981;12(3):515–536. doi: 10.1016/0163-7258(81)90096-6. [DOI] [PubMed] [Google Scholar]
- Senft A. W., Crabtree G. W. Pathways of nucleotide metabolism in Schistosoma mansoni--VII. Inhibition of adenine and guanine nucleotide synthesis by purine analogs in intact worms. Biochem Pharmacol. 1977 Oct 15;26(20):1847–1855. doi: 10.1016/0006-2952(77)90158-7. [DOI] [PubMed] [Google Scholar]
- Smithers S. R., Terry R. J. The infection of laboratory hosts with cercariae of Schistosoma mansoni and the recovery of the adult worms. Parasitology. 1965 Nov;55(4):695–700. doi: 10.1017/s0031182000086248. [DOI] [PubMed] [Google Scholar]