Antitumor efficacy of PD115934 (NSC 366140) against solid tumors of mice.

PD115934 (NSC 366140) is a soluble pyrazoloacridine derivative presently undergoing preclinical toxicology evaluation with the anticipation of Phase I human investigation. The agent displayed both human and murine solid tumor selectivity in vitro in a soft agar disk diffusion assay, relative to its activity against murine L1210 leukemia. In vivo it was highly active against solid tumors colon adenocarcinoma 38 and pancreas ductal carcinoma 03, which was consistent with the cellular cytotoxicity seen in the disk diffusion assay. A log cell kill of greater than 4.0 was demonstrated in vivo against both models. PD115934 was administered by both bolus and infusional therapy. After completion of these trials, it was determined that this compound was a schedule category III agent, i.e., a schedule-independent agent with peak plasma level toxicity. The main toxicity encountered with infusional therapy was myelosuppression. With bolus therapy, central nervous system toxicities were dose limiting. On the basis of our preclinical infusion studies, we recommend a 2-h infusion twice weekly in humans in order to obtain a total dose of 360 mg/m2 over 8 weeks.

Experimental antitumor activity of the amsacrine analogue CI-921.

CI-921 is a di-substituted analogue of amsacrine currently in phase 1 clinical trial. CI-921 was developed to clinical trial largely on the basis of a series of studies at five cancer research laboratories that demonstrated its improved spectrum and degree of activity relative to those of amsacrine against murine tumor models. The tumor models studied included lung, colon, and mammary carcinomas and encompassed a wide range of biologic properties and chemosensitivities. CI-921 had significant activity against 16 of 19 (84%) tumor models examined. The activity of CI-921 was superior to that of amsacrine in 10 of 14 tumor systems that were sensitive to at least one of the agents and for which comparable data existed. In the remaining four systems, CI-921 and amsacrine were equivalent in activity. CI-921 was found to be roughly equipotent with amsacrine on a milligram-per-kilogram (body wt) basis and was found to have significantly higher activity when given orally.

Activity of flavone acetic acid (NSC-347512) against solid tumors of mice.

Flavone acetic acid (FAA) is a new antitumor agent that has recently entered Phase I clinical trials. In preclinical studies, we have found that FAA was broadly active against a variety of transplantable solid tumors of mice (colon #51, #07, #10, #26; pancreatic ductal adenocarcinomas #02 and #03; mammary adenocarcinoma #16/C/Adr; M5076 reticulum cell sarcoma and Glasgow's osteosarcoma). FAA was curative for colon adenocarcinoma #10 and pancreatic ductal adenocarcinoma #03. Thus, for the first time an agent has been identified with very broad, perhaps nearly universal solid tumor activity. FAA was also found to be orally active and stable in solution at 37 degrees C for 48 h. FAA was selectively cytotoxic in vitro for solid tumors over leukemias L1210 and P388 (in a soft-agar colony formation assay), thus correlating cellular selectivity in vitro with in vivo antitumor activity. The finding that FAA was active in vitro, established that the agent did not need metabolism (activation) outside the tumor cell. The main drawback of FAA was an unusual 'threshold' behavior in which only a narrow range of doses were active and splitting the dose markedly decreased activity.

Toxicity and anticancer activity of a new triazine antifolate (NSC 127755).

A new triazine folate antagonist, 3-chloro-4-((4-(2-chloro-4-[4,6-diamino-2,2-dimethyl-s-triazin-1(2H)-yl]phenyl)butyl)) benzenesulfonyl fluoride compounded with ethanesulfonic acid (1:1) (NSC 127755), was highly active against four transplantable colon adenocarcinomas (36, 38, 10/A, 12/A) and the Dunning murine ovarian tumor M5076. Treatment schedule studies indicated that a prolonged time of exposure provided optimum antitumor activity for the compound. The combination of NSC 127755 plus 4-amino-1-[5-O-(1-oxohexadecyl)-beta-D-arabinofuranosyl]-2(1H)-pyrimidinone (palmO-ara-C, NSC 135962) was found to have therapeutic synergism against grossly evident colon adenocarcinoma 36.