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Preclinical antitumor activity of XK469 (NSC 656889)
P M LoRusso1, R Parchment, L Demchik
1Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI 48201, USA.
Abstract:
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.
Insights
XK469, a novel quinoxaline antitumor agent, shows broad efficacy against murine solid tumors and human tumor xenografts. This compound is orally and intravenously effective, with myelosuppression as the dose-limiting toxicity, suggesting potential human tolerability.
Area of Science:
- Oncology
- Pharmacology
- Drug Discovery
Background:
- XK469 is a novel, water-soluble quinoxaline derivative with potential antitumor activity.
- Quinoxaline-based agents represent a promising class of novel chemotherapeutics.
Purpose of the Study:
- To evaluate the in vitro and in vivo antitumor activity of XK469 against various murine and human tumor models.
- To assess the toxicity profile and potential human tolerability of XK469.
Main Methods:
- In vitro cytotoxicity assays against murine cancer cell lines.
- In vivo efficacy studies in mice bearing murine tumors and human tumor xenografts.
- Hematotoxicity assessment using murine and human bone marrow progenitor cells (CFU-GM).
Main Results:
- XK469 demonstrated selective cytotoxicity against murine solid tumor cell lines.
- The compound was active against 7/7 murine tumors and 4/6 human tumor xenografts, administered intravenously and orally.
- Myelosuppression was the dose-limiting toxicity, with rapid recovery observed; human bone marrow progenitors showed comparable tolerance to murine counterparts.
Conclusions:
- XK469 exhibits significant antitumor activity in preclinical models.
- The observed toxicity profile and differential tolerance suggest that humans may tolerate efficacious doses of XK469.