XK469 (NSC 656889) is a water-soluble member of the novel quinoxaline famil
y of antitumor agents. In vitro, XK469 demonstrated selective cytotoxicity
for several murine solid tumors including colorectal and mammary adenocarci
noma cell lines, when compared to both leukemia and normal epithelial cells
. In vivo, XK469 was active against 7/7 murine tumors tested, including pan
creatic ductal carcinomas #02 and #03, colon adenocarcinomas #38 and #51/A,
mammary adenocarcinoma #16/C and the Adriamycin resistant mammary adenocar
cinomas #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 a
denocarcinoma 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 wer
e below curative levels. The dose-limiting toxicity appeared to be myelosup
pression with rapid host recovery (5-8 days), and in vitro assays of XK469
toxicity to murine bone marrow neutrophil progenitors CFU-GM (colony formin
g unit-granulocyte/macrophage) demonstrated concentration-dependent toxicit
y from 0.5-30 mu g/mL. The difference in drug tolerance between BDF1 and SC
ID mice was detected in vitro as a 3-fold difference in the IC90 for CFU-GM
, despite similar IC50 values. Comparative in vitro hematotoxicology studie
s revealed that human bone marrow CFU-GM tolerated XK469 as well as their S
CID counterparts (IC90 values 5.7 vs. 7.4 mu g/mL). Based on comparison wit
h previously tested anti-cancer agents, these data suggest that humans will
be able to tolerate XK469 doses that are efficacious against human tumor x
enografts.