The novel imidazoisoquinoline
SDZ 62-434, originally identified as a
platelet-activating factor (PAF) antagonist, has antiproliferative activity in a range of cell lines from human solid and haematological
malignancies. Using an MTT cytotoxicity assay, IC50 values of 5 microM - 111 microM were observed following a 24 h exposure. Similar results were obtained using a clonogenic assay. The HT29
colon adenocarcinoma was particularly sensitive while the MCF-7
breast carcinoma was the most resistant in our panel. Only a 2-3 fold cross-resistance was seen in the
doxorubicin and
cisplatin resistant variants of the A2780 ovarian
carcinoma; the
drug did not modulate sensitivity to
doxorubicin in either parent or resistant lines. No cross-resistance to
SDZ 62-434 was seen in a
doxorubicin-resistant MCF-7 variant. Cytotoxicity was not due to non-specific membrane lysis. The potent PAF antagonist
WEB 2086 did not modulate
SDZ 62-434 cytotoxicity, indicating no role for
PAF receptors. Precursor incorporation studies in A2780 cells showed that
DNA synthesis was inhibited more effectively than
protein synthesis while
RNA synthesis was unaffected.
SDZ 62-434 inhibited both
bombesin and
platelet-derived growth factor-induced
DNA synthesis in quiescent Swiss 3T3 cells. This suggests a possible role for
SDZ 62-434 as an inhibitor of signal transduction in
cancer cells.