Preclinical antitumor activity of XK469 (NSC 656889)

Citation
Pm. Lorusso et al., Preclinical antitumor activity of XK469 (NSC 656889), INV NEW DR, 16(4), 1998, pp. 287-296
Citations number
24
Categorie Soggetti
Pharmacology,"Pharmacology & Toxicology
Journal title
INVESTIGATIONAL NEW DRUGS
ISSN journal
01676997 → ACNP
Volume
16
Issue
4
Year of publication
1998
Pages
287 - 296
Database
ISI
SICI code
0167-6997(1998)16:4<287:PAAOX(>2.0.ZU;2-X
Abstract
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.