Levodopa and dopamine analogs: dihydroxy and trihydroxybenzylamines as novel quinol antitumor agents in experimental leukemia in vivo.
Levodopa and dopamine demonstrate significant antitumor activity in several experimental systems. We have prepared the nonneurotoxic dihydroxybenzylamine (DHBA) analogs 2,3-DHBA, 3,4-DHBA, and 2,5-DHBA and the trihydroxy derivatives 2,3,4- and 3,4,5-trihydroxybenzylamine. These analogs demonstrated significant and reproducible antitumor activity in the ip P388 and L1210 lymphocytic leukemias. This activity was markedly increased when the drugs were given by multiple injections three times daily for 4 days. 3,4-DHBA and 2,3-DHBA resulted in 30% and 20% long-term survivors, respectively. There was a selective inhibition of thymidine incorporation and a relatively lesser effect on uridine and leucine incorporations. Inhibitory concentrations were between 0.1 and 1.0 mM. The trihydroxy derivatives were more potent, with inhibitory concentrations between 0.01 and 1.0 mM. Furthermore, the trihydroxy derivatives were also able to inhibit the incorporation of uridine and leucine as well as thymidine. The para derivative, 2,5-DHBA, although a potent inhibitor in vitro, was completely inactive in vivo. When L1210 and P388 tumor-bearing animals were given radioactive labeled thymidine in vivo following the administration of drugs. a selective inhibition of thymidine incorporation by tumor cells was observed, with essentially no effect on gut or bone marrow. Doses greater than 200 mg/kg completely suppressed the incorporation of radioactively labeled thymidine by tumor cells 1 hour after administration of drug. A similar dose response was observed in the more slowly growing P388 leukemia, suggesting that the antitumor effect did not strongly correlate with rate of the tumor. Since levodopa and dopamine are currently being evaluated in patients with metastatic melanoma, the availability of analogs with enhanced antitumor activity and broader antitumor spectrum are of interest.
D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D001853:Bone Marrow / Q000378:metabolism; D002478:Cells, Cultured; D004298:Dopamine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004334:Drug Administration Schedule; D007413:Intestinal Mucosa / Q000378:metabolism; D007930:Leucine / Q000378:metabolism; D007942:Leukemia, Experimental / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D007980:Levodopa / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D051379:Mice; D009368:Neoplasm Transplantation; D013936:Thymidine / Q000378:metabolism; D013997:Time Factors; D014529:Uridine / Q000378:metabolism
D000970:Antineoplastic Agents; D007980:Levodopa; D007930:Leucine; D013936:Thymidine; D004298:Dopamine; D014529:Uridine