In 1971, Dr Judah Folkman published the “angiogenic hypothesis” suggesting that
ID: 96086 • Letter: I
Question
In 1971, Dr Judah Folkman published the “angiogenic hypothesis” suggesting that a tumor cannot grow beyond 1–2 millimeters without the development (angiogenesis) of new blood vessels that provide access to oxygen and nutrients. During the 1990s, it was discovered that vascular endothelial growth factor (VEGF) stimulates the proliferation and migration of the cells that form blood vessels, leading to the formation of new blood vessels. VEGF binds to receptor tyrosine kinases (RTKs) on the cell surface and causes the RTKs to dimerize and become active, thereby initiating an intracellular signaling cascade that stimulates cell division and inhibits apoptosis. Many cancer cells secrete high levels of VEGF. Increased VEGF expression in a tumor is correlated with a poor medical outcome for the patient. Some evidence suggests that blocking VEGF-dependent signaling may prevent the formation of new blood vessels and lead to the death of immature blood vessels without disturbing mature blood vessels. You work for a biotechnology company that seeks to create anticancer drugs that prevent the growth of tumors and/or cause tumors to shrink, while leaving normal cells relatively untouched. After learning about VEGF, you have a bright idea for a new mechanism of action for a potential anticancer drug. What is your idea?
Explanation / Answer
1. There are several strategies for using of potential anti-cancer drugs. Some of them are 1. Oligonucleotides 2. Anti-VEGF monoclonal antibodies 3. Soluble VEGF receptor and 4. Small molecule inhibitors.
2. Oligonucleotides: Ribozymes that target the VEGf receptors mRNAs (KDR mRNA) were developed KDR mRNA sites reduces VEGF induced proliferation of cultured human vascular endothelial cells. It also exhibit antiangiogenic activity.
3. Anti-VEGF monoclonal antibodies: Treatment of a Murine monoclonal antibody specific for VEGF will potently suppresse angiogenesis and growth. A recombinant mAb VEGF and rhumAb VEGF version of this antibody are developed in the treatment of solid tumor and other disorders.
4. Soluble VEGF receptor: A soluble recombinant Fit-1 is used to bind to circulating VEGF and inhibit the signaling pathway. Another approach is tumor cells are transfected with cDNA encoding native soluble Fit-1 truncated VEGF receptor which inactivate heterodimers with membrane-spanning VEGF receptors.
5.Small molecule inhibitors: 3-substituted indolinone compound SUS5416 is specific and potent catalytic inhibitor of VEGFR protein kinases. It is specific VEGFR inhibitor which has no inhibitory activity against serine threonine protein kinases and tyrosine kinases.