Pyrazoloacridines, a new class of anticancer agents with selectivity against solid tumors in vitro

Abstract

A series of 2-aminoalkyl-5-nitropyrazolo[3,4,5-kl]acridines (pyrazoloacridines) was evaluated in vitro for activity against a panel of human tumor cell lines of breast, colon, or lung origin. Several pyrazoloacridines were found to possess solid tumor selectivity relative to their activity against murine leukemia L1210 cells as well as human lymphoblastoid cells. The superior compounds in this regard were also found to exhibit excellent activity against primary human tumors in stem cell clonogenic assays. In addition, many of the compounds tested were found to be selectively cytotoxic to hypoxic relative to oxic HCT-8 colon adenocarcinoma cells, a property that may be a consequence of the potentially reducible 5-nitro function. A number of pyrazoloacridines were also found to exhibit potency against noncycling Chinese hamster ovary cells comparable to that observed against actively dividing cultures. Consistent with their favorable activity against nondividing cells, further testing of the pyrazoloacridines revealed that generally less drug is required to inhibit RNA synthesis than DNA synthesis in L1210 cells. Collectively these data indicate that the pyrazoloacridines represent a novel class of antitumor agents which warrant further preclinical evaluation for their potential clinical usefulness in the treatment of solid tumors.