The objective of this study was to determine the tumor distribution of temozolomide, an alkylating agent, in the absence and presence of the angiogenesis inhibitor 3-[(2,4-dimethylpyrrol-5-yl)methylidenyl]indolin-2-one (SU5416), a specific vascular endothelial cell growth factor receptor 2 inhibitor. The study was conducted in nude rats bearing either subcutaneous or intracerebral tumors that overexpressed vascular endothelial cell growth factor. For both tumor locations, animals were assigned to either of two treatment groups, SU5416 (25 mg/kg, dissolved in dimethyl sulfoxide) or vehicle control, dimethyl sulfoxide (710 l/kg) administered i.p. every day for a total of nine doses. Twenty-four hours after the last dose of SU5416 or dimethyl sulfoxide, temozolomide was administrated as a steady-state infusion regimen designed to achieve target plasma concentrations (C p ) of 20 g/ml. In addition to the measurement of temozolomide C p , tumor interstitial fluid unbound concentrations of temozolomide were evaluated by microdialysis. In subcutaneous tumors, SU5416 treatment produced a 24% reduction in steady-state temozolomide C t values (p Ͻ 0.05) as well as 21% reductions in tumor/plasma concentration ratios (C t /C p ; p ϭ 0.11) compared with controls. In intracerebral tumors, steady-state temozolomide C t and C t /C p ratios were significantly increased by 2-fold in the SU5416 treatment group compared with control. The apparent paradoxical effect of SU5416 on the tumor disposition of temozolomide in subcutaneous and intracerebral tumors is discussed in the context of physiological changes (for example, interstitial fluid pressure and microvessel density) and the sampling region in the tumor. It is proposed that the net balance of antiangiogenic drug-mediated pharmacodynamic actions will determine how drug disposition in tumors may be affected.The ability to combine anticancer drugs into effective therapeutic regimens is a cornerstone of successful cancer chemotherapy. A common theme is to combine agents with different mechanisms of action and nonoverlapping toxicities as a means to improve the therapeutic index. The combination of angiogenesis inhibitors and cytotoxic agents represents two classes of drugs that exemplify this latter dogma of combining drugs with different pharmacological targets and different toxicities. Antiangiogenic drugs inhibit endothelial cell proliferation and neovascularization by various mechanisms, with many of the newer agents able to interrupt different growth factor pathways. Cytotoxic drugs target tumor cells and cause cell death through a diverse range of mechanisms, and most often possess a dose-limiting toxicity of myelosuppression. In preclinical models the combination of angiogenesis inhibitors and cytotoxic drugs compared with single agent therapy have shown increased efficacy based on endpoints of tumor growth (Kato et al., 1994;Teicher et al., 1996;Cascinu et al., 1999;Browder et al., 2000). Except for our previous investigations (Devineni et al., 1996;Ma et al., 200...
Targeting intracellular PBRs is a new drug delivery strategy based on the use of low molecular weight drug conjugates that can be administered systemically. It was demonstrated under steady-state conditions that PK11195-GEM possessed a twofold enhancement in brain tumor selectivity compared to GEM alone. This type of target selectivity would allow higher tumor concentrations to be achieved in conjunction with lower drug concentrations in normal or non-target tissues.
Endothelial-to-mesenchymal transition (EndMT) has been shown to contribute to organ fibrogenesis. We have reported that N-acetyl-seryl-aspartyl- lysyl-proline (AcSDKP) restored levels of diabetes mellitus-suppressed FGFR1 (fibroblast growth factor receptor 1), the endothelial receptor essential for combating EndMT. However, the molecular regulation and biological/pathological significance of the AcSDKP-FGFR1 relationship has not been elucidated yet. Here, we demonstrated that endothelial FGFR1 deficiency led to AcSDKP-resistant EndMT and severe fibrosis associated with EndMT-stimulated fibrogenic programming in neighboring cells. Diabetes mellitus induced severe kidney fibrosis in endothelial FGFR1-deficient mice (
FGFR1
fl/fl
; VE-cadherin-Cre:
FGFR1
EKO
) but not in control mice (FGFR1
fl/fl
); AcSDKP completely or partially suppressed kidney fibrosis in control or FGFR1
EKO
mice. Severe fibrosis was also induced in hearts of diabetic FGFR1
EKO
mice; however, AcSDKP had no effect on heart fibrosis in FGFR1
EKO
mice. AcSDKP also had no effect on EndMT in either kidney or heart but partially suppressed epithelial-to-mesenchymal transition in kidneys of diabetic FGFR1
EKO
mice. The medium from FGFR1-deficient endothelial cells stimulated TGFβ (transforming growth factor β)/Smad-dependent epithelial-to-mesenchymal transition in cultured human proximal tubule epithelial cell line, AcSDKP inhibited such epithelial-to-mesenchymal transition. These data demonstrated that endothelial FGFR1 is essential as an antifibrotic core molecule as the target of AcSDKP.
Two new solanapyrone analogues, solanapyrones N and O (1 and 2, resp.), and three known compounds, solanapyrone C (3), nigrosporalactone (4), and phomalactone (5), were isolated from the fermentation culture of Nigrospora sp. YB-141, an endophytic fungus isolated from Azadirachta indica A. Juss. The structures of the new compounds were elucidated on the basis of spectroscopic analysis. The antifungal activities of 1-5 towards seven phytopathogenic fungi were tested. Most of the compounds exhibited no or only weak antifungal activities.
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