A new model to predict antitumor activity of new analogues was developed, and the cross-resistance against
cisplatin (CDDP) and
Adriamycin (ADM) was examined. A preclinical evaluation of various new analogues using this new model was performed. The antitumor activities of KT6149,
MX-2 (KRN8602), SM5887,
menogaril (TUT-7), and
liblomycin (
NK313) were evaluated against four
non-small cell lung cancer cell lines, PC-7, -9, -13, and -14; two
small cell lung cancer cell lines, H69 and N231; four CDDP-resistant cell lines, PC-7/1.0, PC-9/0.5, PC-14/1.5, and H69/0.4; a human
myelogenous leukemia cell line, K562; and its ADM-resistant subline, K562/ADM by clonogenic assay. The relative antitumor activities of these new analogues were compared with those of parental agents,
mitomycin C, ADM,
bleomycin, and several anticancer drugs, CDDP,
daunomycin,
vindesine, and
etoposide. KT6149 was more active than
mitomycin C against all
lung cancer cell lines and the human
myelogenous leukemia cell line.
Menogaril showed greater activity than ADM, and
MX-2 showed activity similar to ADM. However, the antitumor activity of SM5887 was lower than that of ADM. SM5887 and
menogaril showed cross-resistance to K562/ADM. Nevertheless, the antitumor activity against K562/ADM of
MX-2 was similar to that of the parental cell lines. The activity of
liblomycin was similar to that of
bleomycin. Thus, KT6149 appears to be the best analogue for use in a clinical trial against
lung cancer.
MX-2 was active even against ADM-resistant
cancer cells. The values of relative resistance to CDDP or ADM were 4.7, 8.1, 7.5, 20.0, and 13.6 for PC-7/1.0, PC-9/0.5, PC-14/1.5, H69/0.4, and K562/ADM, respectively. CDDP-resistant cell lines showed no cross-resistance with other drugs in this study. K562/ADM showed cross-resistance against
daunomycin,
etoposide, and
vindesine. In contrast,
mitomycin C and
bleomycin had nearly equal activity against K562 and K562/ADM. However, K562/ADM was 2.4-fold more sensitive to CDDP than its parental cell line, K562 (P less than 0.001). These results suggested that the mechanism of CDDP resistance is different from that of multidrug resistance.