Antineoplastics V Flashcards
What three signal transduction inhibitors (STIs) should we know?
- Imatinib
- Erlotinib
- Gefitinib
How do STIs work?
They bind to the ATP-binding site of tyrosine kinases (NOT the substrate binding site).
Why do STIs generally have fewer side effects than conventional therapies?
-They are targeted toward the specific defect in a particular cancer
Ex: 1. Imatinib - to bcr-abl in CML
2. Erlotinib and Gefitinib to EGFR which is overexposed in epithelial-derived cancers
What are the 9 signal transduction inhibitors?
- Bosutinib
- Dasatinib
- Erlotinib
- Gefitinib
- Imatinib
- Nilotinib
- Pazopanib
- Sorafenib
- Sunitinib
Tyrosine Kianses
- Important regulators of intracellular signal transduction pathways, where they are involved in development and multicellular communication
- They phosphorylate tyrosine residues
- Over 1000 different tyrosine kinases have been identified
- More than half of the known receptor protein kinases have been found in either mutated or overexpressed forms that are associated with malignancies
- Both signal transduction inhibitors and antibodies have been designed to interfere with the actions of specific tyrosine kinases
What is the MOA of Bosutinib, Dasatinib, Imatinib, Nilotinib?
- Competitive antagonists at the ATP-binding site of:
- –BCR-ABL: non-receptor tyrosine kinase disregulated by the translocation of its gene from chrom 9 to chrom 22 in most patients with CML
- –C-KIT: tyrosine kinase altered in gastrointestinal stromal tumours (GIST)
- –Platelet-derived growth factor (PDGF) receptor (weak)
DASTAINIB
- Also targets Src, a tyrosine kinase whose expression is unregulated in several types of cancer
- —may be anti-metastatic in epithelial-derived tumors
MOA for Erlotinib (Tarceva/Genetech) and Gefitinib (Iressa/AstraZeneca):
-Competitive antagonists of the ATP-binding site of epithelial growth factor receptor (EGFR) tyrosine kinase, which is overexposed in a large number of epithelial-derived cancers
How does resistance develop to these drugs?
Change in target proteins
- Usually 2ndary resistance due to mutation of ATP-binding site that prevents drug binding in cancer cells, often due to further mutation of bcr-abl gene (heterogeneity of tumor)
- Sometimes see overexpression of bcr/abl or expression of other kinases (primary resistance)
- Bosutinib, Dasatinib and Nilotinib were developed to target cells that have become resistant to imatinib
What is the pharmacokinetics of STIs?
- Oral admin; good bioavailability
- Highly plasma protein bound
- Metabolized in the liver (CYP 3A4), and excreted in the feces (hepatobiliary excretion)
What is the only curative therapy for CML?
Bone marrow transplant (30-50% patients)
-However, patients over 60 do not qualify and not all patients can find donor –> overall cure rate for BMT is under 15%
When was CML discovered and what was the survival time?
- 1900
- 31 months
What was the first treatment for CML in 1960?
Busulfan, Hydroxyurea
- Ph chromosome was discovered
- Drugs kill all rapidly dividing cells
- Survival: 35-67 months
- Success rate: 42% hematologic
What treatment for CML was discovered in 1980?
Interferon alpha
- Bcr-Abl gene was discovered
- Decreases cell proliferation
- Survival: 55-89 months
- Success rate: 20-30% cytogenic, 80% hematologic
What treatment for CML was discovered in 2001?
Imatinib –> designed to be used for CML!!
- Tyrosine kinase inhibitor was discovered
- Drug suppresses defective enzyme in cancer cells
- Survival: >5 years
- Success rate: 50-95% cytogenic
What are the therapeutic uses of Bosutinib, Imatinib, Dasatinib, Nalotinib?
- Complete hematological and cytological response in 85-95% of patients in the chronic phase of CML
- Delay death in 25% of patients in blast crisis (75% of these patients initially respond)
- Gastrointestinal stromal tumors expressing c-kit
What are the therapeutic uses of Erlotinib, Gefitinib?
- Metastatic non-small cell lung cancer (NSCLC) after failure of standard chemotherapies
- Different populations experiencing varying efficacies:
- –25% of NSCLC cases in Japan respond, but 10% of cases in US
- –Non-smokers and broncho-alveolar subtype do better
- –>Having the “right” mutation (we don’t know what it is) means the difference between a “cure” and no response
What are the toxicities for STIs in general?
- Much less nausea, vomiting than cytotoxic cells
- 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
- –More common and more severe with DASATINIB, IMATINIB, and NILOTINIB because Abl tyrosine kinases are necessary for normal heart function
- TERATOGENIC
What are the specific toxicities for Imatinib, Erlotinib and Gefitinib?
Imatinib: edema, bone marrow suppression
Erlotinib and Gefitinib: Rare interstitial pneumonia (which can be fatal)
What is Imatinib usually used for?
CML
What is Erlotinib/Gefitinib usually used for?
NSCLC
How well do we understand the genetic defect with Imatinib and Erlotinib/Gefitinib?
- Imatinib - Excellent
- Erlo/Gefit - Poor
Are there “likely responders”/homogeneity of disease process among candidate patients to Imatinib and Erlotinib/Gefitinib?
Imat - Yes, among patients in chronic phase
Erlo/Geftit - No
Is there uniqueness of the drug target (molecular markers) in imatinib and erlotinib/gefitinib?
Imat - Only in cancer cells
Erlo/Gefit - In many normal and cancer cells
Is there large scale success in treatment with Imatinib and Erlotinib/Gefitinib?
Imatinib - yes
Erlotinib/Gefitinib - Not really (fails more often than it works)
