Effects of Fostriecin on Cells

Fostriecin has demonstrated marked antitumor activity against a wide spectrum of tumor cells in vitro and in vivo. In cultured tumor cells, fostriecin proved cytotoxic against a number of cell lines (i.e., L1210, HCT-8, P338), and structure-activity relationship studies comparing fostriecin analogs and cytotoxicity indicate that both the lactone ring and phosphate group are important for cytotoxicity of fostriecin in vitro (Lewy et al. 2002). Recently, the total synthesis of fostriecin has been reported (Boger et al. 2001), so analogs for further evaluation should be forthcoming (Lewy et al. 2002).

In mice, fostriecin exhibits potent cytotoxic activity P388 and L1210 leu-kemias when administered via i.p. injection. Fostriecin was also active against B16 melanomas. In vitro, fostriecin proved efficacious in L1210-bearing mice with an IC50 of 0.46 mM for continuous exposure and 4.4 mM for a 1-h exposure. Scheduling studies indicated that once-daily treatment for 5- or 9-day periods was more effective then two or three single doses every 4 days, and i.p. dosing at 6.25 mg/kg per day on days 1-9 proved to be curative in the L1210 mouse model (de Jong et al. 1997).

In a clonogenic human solid tumor screening assay, in which fostriecin (2.2 mM for 1 h) was tested on a number of tumor specimens derived from patients, fostriecin was found to be highly active and compared favorably to 17 clinically used anticancer drugs including etoposide and doxorubicin (de Jong et al. 1997). Fostriecin produced a 50% or greater decrease in tumor colony forming units in 42% of breast, 33% of the ovarian, and 38% of the non-small cell lung cancer samples (de Jong et al. 1997). In solid tumor mice models, fostriecin produced rapid necrosis in advanced implanted murine colon tumors (Baguley et al. 1989). In other studies, fostriecin proved inactive against a range of solid tumors; however, because the tumors were also insensitive to methotrexate this failure was attributed to the absence of the reduced-folate carrier (de Jong et al. 1997).

Another interesting development is that fostriecin was shown to provide protection to ischemic cardiac tissue comparable to that produced by ischemic preconditioning. Ischemic preconditioning is a phenomenon whereby the heart is protected from an ischemic insult by a previous brief episode of ischemia and reperfusion. Although the mechanism of the protection provided by ischemic preconditioning has remained elusive, several lines of evidence suggest that the activation of protein kinases, such as protein kinase C (Weinbrenner et al. 1998) and the p38 MAPK cascade (Ytrehus et al. 1994) may contribute to this protective response (for review see; Downey and Cohen 1997). To test the potential of fostriecin as an inhibitor of ischemic damage, studies were conducted in perfused, isolated rabbit hearts (Weinbrenner et al. 1997) and isolated ventricular cardiomyocytes from rabbit (Armstrong et al. 1997; Weinbrenner et al. 1997; Armstrong et al. 1998) and pig (Armstrong et al. 1997, 1998). In both pig and rabbit models 0.1-10 ^M fostriecin mimicked the protection of preconditioning in both rabbit and pig cardiomyocytes (Armstrong et al. 1997, 1998; Weinbrenner et al. 1997). In isolated, perfused rabbit hearts fostriecin was administered starting either 15 min prior to or 10 min after the onset of a 30-min period of regional ischemia and continuing until the onset of reperfusion. In hearts pretreated with fostriecin, only 8% of the ischemic zone infarcted, which was significantly less than that in the untreated control hearts (33%). Fostriecin also provided significant protection in hearts treated only after the onset of ischemia (18% infarction; p<0.05 vs control). Together, these studies suggest that type-selective phosphatase inhibitors may also offer promise as infarct size-limiting drugs.

Was this article helpful?

0 0
Cigarette Crusher

Cigarette Crusher

Get All The Support And Guidance You Need To Permanently STOP Being A Slave To Nicotine And Cigarettes. This Book Is One Of The Most Valuable Resources In The World When It Comes To Easy Ways To Eliminate Smoking Addiction And Revitalize Your Body.

Get My Free Ebook

Post a comment