EFFECTS OF NEW ANTITUMOR BIFUNCTIONAL INTERCALATORS DERIVED FROM 7H-PYRIDOCARBAZOLE ON SENSITIVE AND RESISTANT L1210 CELLS

Abstract

The antitumor properties of 7H-pyridocarbazole dimers, a new series of bifunctional intercalators, were recently described. In order to study the mechanism of action of these compounds, an L1210 subline was made resistant to 1 dimer (NSC 335153; ditercalinium). Selection of resistant cells was based on an in vitro-in vivo procedure as follows. Ascitic cells were taken from a leukemic mouse and incubated in vitro with the dimer for 1 h. They were then injected into mice. After the development of the ascites, L1210 cells were collected and the process was repeated 13 times, until establishment of the resistance. Cloned resistant cells have maintained their resistance for 18 mo. of in vitro culture. The effects of 2 dimers (NSC 335153 and NSC 335154) on cell viability, growth, colony formation and cell cycle progression were investigated on parental and resistant L1210 cells. The cross-resistance of these 2 L1210 cell lines to several cytotoxic agents was estimated. Several observations indicate that the mechanism of action of these dimers might be different from that of monointercalating agents: these drugs induce a delayed toxicity (growth arrest occurring 5 generations after drug exposure) in sensitive but not in resistant cells; cells exposed to the dimers arrested almost randomly in all phases of the cell cycle, whereas the corresponding monomer provokes a block in the G2 + M phase. Resistant cells were cross-resistant to 7H-pyridocarbazole monomer, Adriamycin and vincristine but not to 6H-pyridocarbazole monomer derivatives actinomycin D and methotrexate.