The chemical derivatization of biologically active microbial metabolites continues to be a promising approach to the identification of new drugs. We recently synthesized the novel antiproliferative compound
SDZ 281-977, 5-[2-(2,5-dimethoxy-phenyl)ethyl]-2-hydroxy-
benzoic acid methylester, a derivative of the
EGF receptor tyrosine kinase inhibitor lavendustin A. Here we report on our studies of the anticancer efficacy and the mode of action of
SDZ 281-977. The growth of both the human pancreatic
tumor cells MIA PaCa-2 and the human vulvar
carcinoma cells A431 was inhibited in the low micromolar range.
Tumors from these cells were induced in nude mice and were shown to respond to orally or intravenously administered
SDZ 281-977. In contrast, no antitumor effect was detected in rats bearing dimethylbenzanthracene-induced mammary
tumors. Studies in mice indicated that
SDZ 281-977 was neither immunosuppressive nor hematosuppressive at doses effectively inhibiting
tumor growth. Surprisingly, the mode of action of
SDZ 281-977 apparently does not involve inhibition of
EGF receptor tryosine
kinase, because, in contrast to
lavendustin A,
SDZ 281-977 failed to inhibit this
enzyme in a cell-free assay. The mechanism of the antiproliferative effect can be explained on a cellular level by the ability of the compound to arrest cells in mitosis.
SDZ 281-977 is thus the first example of an
antimitotic agent derived from the potent
tyrosine kinase inhibitor lavendustin A. The therapeutic potential of
SDZ 281-977 is enhanced by the fact that it is not subject to multidrug resistance, because
tumor cells expressing the multidrug resistance phenotype were as sensitive to
SDZ 281-977 as their nonresistant counterparts. In conclusion,
SDZ 281-977 represents a novel
lavendustin A derivative with potent antiproliferative properties in vitro and in vivo that may be explained on the basis of its
antimitotic effects.
SDZ 281-977 may be a candidate
drug for the treatment of selected
cancers, including those expressing the multidrug resistance phenotype.