The search for
cancer therapies that are more selective for
tumor cells and spare normal sensitive cells has been very active for at least 20 years. The extracellularly
tumor-activated peptidic
prodrug of
doxorubicin (Dox)
CPI-0004Na (N-succinyl-beta-alanyl-L-leucyl-L-alanyl-L-leucyl-Dox) is potentially such a treatment. Here, we report the results of lethality studies performed with this compound in the mouse, showing that it is up to 4.6 times less toxic than Dox.HCl by the i.v. route and up to 16.2 times after i.p. administration. Pharmacokinetics and tissue distribution data indicate that this reduced toxicity is attributable to a lower uptake of Dox in normal tissues
after treatment with
CPI-0004Na than after the administration of an equimolar dose of Dox.HCl. For example, heart exposure to Dox is reduced >10-fold. Because of this reduced toxicity, higher doses of
CPI-0004Na than of the parent
drug could be used to treat nude mice bearing s.c. human breast (MCF-7/6) and colon (LS-174-T and CXF-280/10)
tumors. In all three models, the
prodrug showed a much improved efficacy as compared with Dox.HCl. Particularly, LS-174-T
tumors that do not respond to Dox were inhibited by 68%
after treatment with
CPI-0004Na. Tissue distribution studies performed with MCF-7/6
tumor-bearing nude mice and comparing
CPI-0004Na and Dox.HCl confirmed that the improved activity of the
prodrug is actually the result of selective generation and uptake of Dox at the
tumor site. Dox levels in
tumor tissue were 2-fold higher
after treatment with
CPI-0004Na than
after treatment with an equimolar dose of Dox.HCl, whereas normal tissue levels were reduced 1.4-29-fold.