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

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.

Enhancement of alkylating agent activity in vitro by PD 128763, a potent poly(ADP-ribose) synthetase inhibitor.

The ability of DNA repair inhibitors to potentiate alkylating agent cytotoxicity was explored with PD 128763, a dihydroisoquinolinone known to effectively inhibit poly(ADP-ribose) synthetase. The cytotoxic activity of streptozotocin in L1210 leukemia cells was maximally potentiated (7-fold decrease in IC50) under conditions of 24 hr exposure to PD 128763 following treatment with the alkylating agent for 1 hr. Similar treatment conditions resulted in a much greater effect (36-fold enhancement in activity) for the 2-nitroimidazole RSU 1069. In contrast, 3-aminobenzamide was only weakly effective at enhancing activity of either streptozotocin or RSU 1069 (2-3 fold potentiation). However, PD 128763 was ineffective at potentiating the cytotoxicity of the bifunctional alkylating agents carmustine (BCNU) and lomustine (CCNU). Our results are consistent with a role for (poly-ADP) ribosylation in the repair of monofunctional alkylating agent damage. This study supports further exploration of the combination of PD 128763 and RSU 1069 as a potentially useful chemotherapeutic regimen.

Effect of PD 128763, a new potent inhibitor of poly(ADP-ribose) polymerase, on X-ray-induced cellular recovery processes in Chinese hamster V79 cells.

The modifying effects of PD 128763 (3,4-dihydro-5-methyl-1(2H)-isoquinolinone), a potent inhibitor of poly(adenosine-diphosphate (ADP)-ribose) polymerase, on radiation-induced cell killing were examined in Chinese hamster V79 cells. This compound has an IC50 value against the purified enzyme approximately 50X lower than 3-aminobenzamide (3-AB), a widely used specific inhibitor of the enzyme. Exposure of exponentially growing cells to a noncytotoxic concentration (0.5 mM) of PD 128763 for 2 h immediately following X irradiation increased their radiation sensitivity, modifying both the shoulder and the slope of the survival curve. When recovery from sublethal damage and potentially lethal damage was examined in exponential and plateau-phase cells, respectively, postirradiation incubation with 0.5 mM PD 128763 was found not only to inhibit both these processes fully, but also to enhance further the level of radiation-induced cell killing. This is in contrast to the slight effect seen with the less potent inhibitor, 3-AB. The results presented suggest that the mechanism of radiosensitization by PD 128763 is related to the potent inhibition of poly(ADP-ribose) polymerase by this compound.