thioinosine and 5-benzylacyclouridine

Schistosoma mansoni incorporated tubercidin, nebularine, 9-deazaadenosine, 5'-deoxy-5'-iodo-2-fluoroadenosine, 7,9-dideaza-7-thiaadenosine and toyocamycin but not sangivamycin, 3'-deoxy-sangivamycin, or 1-methylformycin into their nucleotide pool after a 4-hr incubation in vitro. In contrast to mammalian systems, addition of nucleoside transport inhibitors nitrobenzylthioinosine 5'-monophosphate (NBMPR-P), dilazep, or benzylacyclouridine had no significant effect on the pattern of incorporation of these adenosine analogues. Dipyridamole, on the other hand, reduced, but did not prevent, the incorporation of these analogues into the nucleoside 5'-triphosphate pool. These results suggest that the transport of purine nucleosides in schistosomes is different from that of their mammalian hosts. Therefore, coadministration of a specific nucleoside transport inhibitor with tubercidin, nebularine, 9-deazaadenosine, 5'-deoxy-5'-iodo-2-fluoroadenosine, toyocamycin, or 7,9-dideaza-7-thiaadenosine may result in high selective toxicity against schistosomes, as was the case with the combination of tubercidin plus NBMPR-P [el Kouni et al., Proc. natn. Acad. Sci. U.S.A. 80, 6667 (1983); el Kouni et al., Biochem. Pharmac. 34, 3921 (1985)], by protecting the host but not the parasite from the toxicity of these analogues.

Topics: Adenosine; Animals; Biological Transport; Dilazep; Dipyridamole; Kinetics; Nucleosides; Schistosoma mansoni; Structure-Activity Relationship; Thioinosine; Thionucleotides; Uracil

In contrast to their effects on mammalian cells, the nucleoside transport inhibitors nitrobenzylthioinosine 5'-monophosphate (NBMPR-P) dilazep, benzylacyclouridine (BAU), and to a lesser extent, dipyridamole have no significant effect on the in vitro uptake of adenosine analogues by Schistosoma mansoni [el Kouni and Cha, Biochem. Pharmac. 36, 1099 (1987)]. Coadministration of either NMBPR-P or dilazep with potentially lethal doses of tubercidin (7-deazaadenosine), nebularine or 9-deazaadenosine protected mice from the toxicity of these adenosine analogues. Dipyridamole caused partial protection, whereas BAU did not protect the animals from this toxicity. Toyocamycin caused delayed mortality (after 16 weeks) which could not be prevented by coadministration of NBMPR-P. In S. mansoni infected mice, treated with the combination of NBMPR-P and 9-deazaadenosine was not effective against the parasite. On the other hand, the combinations of NBMPR-P or dilazep with either tubercidin or nebularine were highly toxic to the parasite but not the host. Combination therapy caused a marked reduction in the number of pairing of worms. Effectiveness of combination therapy could also be noted by a drastic decrease in the number of eggs in the liver and small intestine. All eggs found were dead, indicating a direct effect on ovigenesis. Although dipyridamole was less effective than NBMPR-P or dilazep in protecting the host from the toxicity of tubercidin or nebularine, the combinations with dipyridamole produced similar significant therapeutic effects in animals that survived. Mice receiving the combination of tubercidin (or nebularine) plus NBMPR-P or dilazep, as well as those that survived the combination with dipyridamole, appeared healthy and were found to have normal size livers and spleens. These results suggest that highly selective toxicity against schistosomes can be achieved by coadministration of various nucleoside transport inhibitors with adenosine analogues.

Topics: Adenosine; Animals; Biological Transport; Dilazep; Dipyridamole; Drug Therapy, Combination; Female; Mice; Purine Nucleosides; Ribonucleosides; Schistosoma mansoni; Schistosomiasis; Thioinosine; Thionucleotides; Toyocamycin; Tubercidin; Uracil