LEVODOPA AND DOPAMINE ANALOGS - DIHYDROXY AND TRIHYDROXYBENZYLAMINES AS NOVEL QUINOL ANTI-TUMOR AGENTS IN EXPERIMENTAL LEUKEMIA INVIVO

  • 1 January 1981
    • journal article
    • research article
    • Vol. 65  (9-10) , 861-867
Abstract
L-Dopa and dopamine demonstrate significant antitumor activity in several experimental systems. 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 were prepared. These analogs demonstrated significant and reproducible antitumor activity in the i.p. P388 and L1210 [mouse] lymphocytic leukemias. This activity was markedly increased when the drugs were given by multiple injections 3 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 0.1-1.0 mM. The trihydroxy derivatives were more potent, with inhibitory concentrations between 0.01-1.0 mM. 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 radioactively 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 > 200 mg/kg completely suppressed the incorporation of radioactively labeled thymidine by tumor cells 1 h 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 growth rate of the tumor. Since L-dopa 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.

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