XK469 (NSC 656889) is a water-soluble member of the novel
quinoxaline family of
antitumor agents. In vitro,
XK469 demonstrated selective cytotoxicity for several murine solid
tumors including colorectal and mammary
adenocarcinoma cell lines, when compared to both
leukemia and normal epithelial cells. In vivo,
XK469 was active against 7/7 murine
tumors tested, including
pancreatic ductal carcinomas #02 and #03,
colon adenocarcinomas #38 and #51/A, mammary
adenocarcinoma #16/C and the
Adriamycin resistant mammary
adenocarcinomas #16/C/ADR and #17/ADR.
XK469 was efficacious both intravenously and orally. Regardless of dosing schedule, conventional mice tolerated higher total doses than SCID or nu/nu mice did. Despite these reduced doses,
XK469 was active against xenografts of 4/6 human
tumor lines including mammary
adenocarcinoma MX-1, the
small cell lung cancer DMS 273, the prostate model LNCaP and the CNS
tumor SF295. The lower doses in the xenograft studies were below curative levels. The dose-limiting toxicity appeared to be myelosuppression with rapid host recovery (5-8 days), and in vitro assays of
XK469 toxicity to murine bone marrow neutrophil progenitors CFU-GM (colony forming unit-granulocyte/macrophage) demonstrated concentration-dependent toxicity from 0.5-30 microg/mL. The difference in drug tolerance between BDF1 and SCID mice was detected in vitro as a 3-fold difference in the IC90 for CFU-GM, despite similar IC50 values. Comparative in vitro hematotoxicology studies revealed that human bone marrow CFU-GM tolerated
XK469 as well as their SCID counterparts (IC90 values 5.7 vs. 7.4 microg/mL). Based on comparison with previously tested anti-
cancer agents, these data suggest that humans will be able to tolerate
XK469 doses that are efficacious against human
tumor xenografts.