Angiogenesis Inhibitors / VEGF & mTOR inhibitors / Bevacizumab
Signal Transduction Inhibitors of VEGF-R: PAZOPANIB, SORAFENIB, SUNITINIB
- the receptors for VEGF and PDGF are receptor tyrosine kinases (RTKs)
- 3 of the FDA-approved signal transduction inhibitors are antagonists of VEGF-R and PDGF-R
- PAZOPANIB, SORAFENIB, and SUNITINIB are much less specific than IMATINIB (i.e., they block multiple kinases)
- in addition to blocking VEGF-R and PDGF-R, they also inhibit:
- SORAFENIB: Raf
- PAZOPANIB, SUNITINIB: c-KIT
- these drugs are approved as 1st line treatment for renal cell carcinoma
and several other cancers
- these drugs are highlighted in the controversy over the high cost of new cancer treatments
- SUNITINIB is one of the most expensive drugs ever marketed, especially since it is a drug that doesn't cure cancer but "only" prolongs life
- the estimated cost is $85,000/life year added --- and usually it only extends life by a matter of weeks
- in a recent survey on the impact of cost on treatment, approximately 25% of patients with insurance said that they postponed or declined treatment because of cost
- pharmacokinetics are the same as for STIs that block Bcr-Abl and HER2:
- oral administration; good bioavailability
- highly plasma protein bound
- metabolized in the liver (CYP 3A4), and excreted in the feces (hepatobiliary excretion)
- they exhibit the same general toxicities as STIs that block Bcr-Abl and HER2:
- relatively minor side effects (esp. compared to conventional therapies that work by preventing rapid cell growth): nausea, vomiting, fatigue, myalgia, diarrhea, skin rashes and acne, drug interactions
- can cause congestive heart failure and decreased left ventricular ejection fraction (causing shortness of breath, palpitations, fatigue) and/or myocardial infarction
- incidence and severity vary widely within STIs; less severe for these agents
- teratogenic
- in addition, FOR THESE STIs, specific side effects include:
- PAZOPANIB: severe (fatal) hepatotoxicity, hemorrhage, QT prolongation and torsades de points, GI perforation and hypertension
- SORAFENIB: increased risk of hemorrhage, hypertension
- SUNITINIB: skin discolouration, hand-foot syndrome (palmar-plantar erythrodysesthesia)