PTT.119 [p-F-Phe-m-bis-(2-chloroethyl)amino-L-Phe-Met ethoxy HCl], a new synthetic tripeptide, was highly effective against the
L-phenylalanine mustard (
L-PAM) resistant (L1210/
L-PAM and P388/
L-PAM)
tumor lines, as well as the sensitive
L1210 leukemia. Cytolytic activity of
PTT.119 against all three
leukemias was significantly greater than equimolar doses of
L-PAM. These in vitro results paralleled the significant increases in mean survival times of hosts and, in some cases, abrogations of
tumor formation observed in the in vivo bioassays of PTT.119-treated L1210 and L1210/
L-PAM cells. Dose-response studies failed to demonstrate cross-resistance to the tripeptide by
L-PAM resistant cells. Doses of
PTT.119 required to reduce the viable fraction by 50% (tissue culture dose 50, TCD50) or 100% (TCD100) were 1.3- to 3-fold lower for the
L-PAM resistant cells than for the
L1210 leukemia. In comparison,
L-PAM was unable to completely eliminate cell survival; 0.2 to 3% of the cells in all three
leukemias remained viable even at doses of 75 and 163 microM. In similar studies,
L1210 leukemia cells made resistant to
methotrexate (L1210 MTX) and
cisplatin (L1210DDP) were also completely susceptible to
PTT.119; TCD50 values of the two resistant lines were 1.94 microM for L1210 MTX and 0.525 microM for L1210DDP compared to 2.38 microM for the susceptible parent L1210S
leukemia. Continuous low-dose
PTT.119 treatment of MJY-alpha mammary
tumor cells for 8 months and exposure of
L1210 leukemia to escalating levels of tripeptide for over 100 passages failed to select or induce
drug-resistant phenotypes in either cell line.
PTT.119 appears to be a poor
mutagen and is unlikely to readily increase the probability of
drug-resistant mutants in the
tumor cell populations.