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Flashcards in Antineoplastics V Deck (25)

What three signal transduction inhibitors (STIs) should we know?



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?



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)



-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?

-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


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?



What is Erlotinib/Gefitinib usually used for?



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)