Original ArticlesInhibition of Angiogenesis by Thalidomide Requires Metabolic Activation, Which Is Species-dependent
Section snippets
Materials
Thalidomide was obtained from EntreMed. Suramin was obtained from the Developmental Therapeutics Program, NCI. Doxorubicin and reagents for the NADPH-generating system were purchased from Sigma. TNP-470 was a gift from Takeda Chemical Industries, Ltd. All drugs were prepared as stock solutions in DMSO (Sigma). The concentrations of the stock solutions were prepared so that the final amount of DMSO that was present in the culture medium was 0.5% (v/v). Human liver microsomes were a gift from J.
Metabolism
All microsomal preparations demonstrated metabolic cytochrome P450 activity. Upon incubation of 250 μg/mL of a 200 μg/mL solution of 7-ethoxycoumarin in the presence of 0.25 mg of rat microsomal preparation, 10.16 μg/mL of the metabolite umbelliferone was formed. Likewise, upon incubation of an 80 μg/mL solution of 7-ethoxycoumarin in the presence of 0.1 mg of human and rabbit microsomal preparation, 2.66 and 1.14 μg/mL of umbelliferone was formed. Umbelliferone was not present in any of the
Discussion
Folkman and colleagues 16, 17have demonstrated that angiogenesis is a prerequisite for expansion of solid tumors beyond 1–3 mm3 and have suggested that angiogenesis is often activated during the early, preneoplastic stages in the development of a tumor. Thus, inhibition of angiogenesis should be effective in inhibiting the growth of a malignancy. D’Amato et al. [5]reported that oral thalidomide, a potent teratogen, is a highly effective inhibitor of angiogenesis in the rabbit cornea micropocket
Acknowledgements
Research was funded by the U.S. Government.
References (27)
Thalidomide promotes metastasis of prostate adenocarcinoma cells (PA-III) in L-W rats
Cancer Lett
(1996)- et al.
Induction of morphological differentiation in the human leukemic cell line K562 by exposure to thalidomide metabolites
Leukemia Res
(1991) - et al.
Purification and characterization of hepatic microsomal cytochrome P-450
Pharmacol Ther
(1990) - et al.
Automated high-performance liquid chromatographic assay for the determination of 7-ethoxycoumarin and umbelliferone
J Chromatogr
(1992) - et al.
Recombinant human erythropoietin stimulates angiogenesis in vitro
Kidney Int
(1995) - et al.
Patterns and emerging mechanisms of angiogenic switch during tumorigenesis
Cell
(1996) - et al.
Determination of the thalidomide analogues 2-(2,6-dioxopiperidine-3-yl)phthalimidine (EM 12), 2-(2,6-dioxopiperidine-4-yl)phthalimidine (EM 16) and their metabolites in biological samples
J Chromatogr
(1989) - et al.
Determination of thalidomide and its major metabolites by high-performance liquid chromatography
J Chromatogr
(1987) - et al.
A reversed-phase high performance liquid chromatography method using solid phase extraction to quantitate thalidomide in human serum
Anal Chim Acta
(1997) Tumor angiogenesisTherapeutic implications
N Engl J Med
(1971)
Tumor angiogenesis and metastasis–correlation in invasive breast carcinoma
N Engl J Med
Tumor angiogenesis correlates with metastasis in invasive prostate carcinoma
Am J Pathol
Angiogenesis as a predictor of long-term survival for patients with node-negative breast cancer
J Natl Cancer Inst
Cited by (312)
Toxicologic pathology of the reproductive system
2022, Reproductive and Developmental ToxicologyThalidomide
2022, Reproductive and Developmental ToxicologyCan preclinical drug development help to predict adverse events in clinical trials?
2022, Drug Discovery TodayModeling of differentiation pattern formation in human induced pluripotent stem cells mediated by BMP4 and its inhibitor noggin secreted from cells
2021, Biochemical Engineering JournalThalidomide and analogues
2019, Imides: Medicinal, Agricultural, Synthetic Applications and Natural Products ChemistryVertebrate embryos as tools for anti-angiogenic drug screening and function
2017, Reproductive ToxicologyCitation Excerpt :Explanations for the apparent resistance of rodents to thalidomide include that rodents may produce more efficient antioxidants against free radicals, thalidomide has a shorter half-life in rodents and does not appear to induce apoptosis as it does in humans [134–136]. Another factor may be differences in metabolism and clearance rates of the drug [36,137–139]. Indeed, a recent paper using a transgenic mouse line where CYP3 metabolic enzymes were missing from the placenta resulted in mouse embryos with some thalidomide-induced defects [140].