A new synthetic tripeptide (p-F-Phe-m-bis-(2-chloroethyl)amino-Phe-Met ethoxy HCl),
PTT.119, was demonstrated to have significant cancericidal activity against seven in vitro tumor cell lines of different origins and etiologies and against primary human AMML, ALL, and
hairy cell leukemias. Viabilities of each murine
tumor and rabbit, marmoset, and human
leukemia and
lymphoma line were significantly reduced by treatment with 1-50 micrograms
PTT.119 in media containing serum. Continuous 24-h exposure or pulse treatment as short as 15 and 30 min with the tripeptide resulted in irreversible damage to the
tumor cells. Under identical treatment conditions, freshly isolated human leukemic cells, particularly ALL lymphoblasts, were even more susceptible to
PTT.119 than any of the tested
tumor cell models. Examination of the parameters of
PTT.119 activity revealed that reductions of
tumor cell survival were dependent on the concentration of the tripeptide. Prolongation of
PTT.119 exposure from 15 min to 24 h increased the rates of
tumor cell death but did not proportionally reduce the numbers of surviving cells. Assessment of
tumor cell viabilities for 5 consecutive days following pulse exposure to
PTT.119 demonstrated increasing reductions in
tumor cell survival, which were greatest 5 days
after treatment of
PTT.119 was compared with its three parental components either as individual agents or as a mixture. Both the
alkylator moiety, m-sarcolysin (m.L.SL) alone or together with p-fluoro-
phenylalanine and
L-methionine ethoxy HCl, and
L-PAM (
L-phenylalanine and
L-methionine ethoxy HCl, and
L-PAM (
L-phenylalanine mustard), the p-isomer of m.L.SL, were 1,5- to 3-fold less cytotoxic to
L1210 leukemia and MJY-alpha mammary
tumor cells than
PTT.119. Covalent linkage of the
amino acid residues to m.L.SL yielded a molecule with greatly augmented cancericidal activity capable of acting against a broad spectrum of
tumor cells.