Bisimidazoacridones and related compounds: new antineoplastic agents with high selectivity against colon tumors.

A new class of potent and highly selective antitumor agents has been synthesized. Bisimidazoacridones, where the tetracyclic ring systems are held together by either a N2-methyldiethylenetriamine or 3,3'-diamino-N-methyldipropylamine linker, and related asymmetrical compounds, where one of the imidazoacridone ring system was replaced by a triazoloacridone ring system, were found to be cytostatic and cytotoxic in vitro. Some of these compounds, such as 5,5'-[(methylimino)bis(3,1-propanediylimino)]bis[6H-imidazo[ 4,5,1-de]acridin-6-one] (4b) showed remarkably high activity and selectivity for colon cancer in the National Cancer Institute screen. This antitumor effect was also apparent in colony survival assays utilizing the colon cancer line, HCT-116, and in in vivo assays involving xenografts of tumor derived from HCT-116 in nude mice. The tested compounds exhibited relatively low acute toxicity and were well-tolerated by the treated animals. The bisimidazoacridones interact with nucleic acids in vitro but preliminary experimental and modeling data indicate that in spite of their structure, they may not be bis-intercalators. While the precise mode of action of these compounds is not yet understood, they appear to be excellent candidates for clinical development.

Prevention of tumors in rats by cross-protective immunization.

F344 inbred were repeatedly immunized (days 0, 28, and 42) with normal syngeneic or allogeneic rat tissues or transplantable syngeneic or allogeneic rat tumors (some of which were virus producing). Immunized rats were challenged by sc injection of 10(5) or 10(6) syngeneic rat tumor cells from either of two different tumor lines. Successful cross-protective immunization prevented tumor development in rats that were challenged at 100-1,000 times the 50% tumor dose. The protection was essentially lifelong and complete in that no tumors appeared up to 200 days post challenge in some experiments. To be successful, the tumor cell vaccines had to express a complement-fixing cross-reacting antigen detected with sera from rats bearing any of several different tumors and to be able to induce a spontaneously regressing tumor in the host.

Prevention of 3-methylcholanthrene-induced fibrosarcomas in rats pre-inoculated with endogenous rat retrovirus.

Weanling Fischer 344 rats received a single intraperitoneal injection of a 1000-fold concentrated preparation of endogenous nontransforming rat retrovirus. Ten days later, the rats were each given a single subcutaneous injection of 3-methylcholanthrene. The rats inoculated with the endogenous rat retrovirus were significantly protected against the development of cancer, whereas uninoculated rats and rats given one of several murine retroviruses or baboon retrovirus were not protected.

Prevention of transplantable tumors by adoptive transfer of spleen cells from immunized rats.

Fischer 344 rats were specifically hyperimmunized with allogeneic, nonvirus-producing [Kirsten murine sarcoma virus (KiMSV)] or syngeneic, virus-producing [KiMSV (Rasheed)] rat tumors. Spleen cells taken from these rats adoptively transferred protection against a 100 to 1,000 X rat tumor dose50 cell challenge with several different transplantable rat tumors. Protection was obtained with spleen cells after removal of adherent cells and macrophages but not peritoneal cells. The spleen cells were not directly cytotoxic but required more than 3 days residence in the recipient before protecting the recipient against challenge. No protection against tumor cell challenge was observed when spleen cells were lethally x-ray irradiated before injection into nontreated rats. Spleen cells taken from rats immunized with normal histocompatibility antigens did not protect in this test system.

Induction of rat sarcomas in rats treated with antithymocyte sera after transplantation of human cancer cells.

Human cancer cells that had had high (greater than 160) tissue culture passages, when transplanted into antithymocyte-treated F344 newborn rats, caused induction of rat sarcomas in the rats within 2 or 3 subcultures, whereas human cancer cells with low (5-33) passages in vitro did not cause overt induction of rat sarcomas until after 5-10 subtransplantations. Because oncornavirus activity was not detected in either rat or human tumors, it is suggested that transforming sequences located on the human tumor cells may have been transferred to supporting rat reticulum cells in close contact with the human cancer cells.