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Flashcards in Antineoplastics V Deck (25)
1

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

-Imatinib
-Erlotinib
-Gefitinib

2

How do STIs work?

They bind to the ATP-binding site of tyrosine kinases (NOT the substrate binding site).

3

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

4

What are the 9 signal transduction inhibitors?

-Bosutinib
-Dasatinib
-Erlotinib
-Gefitinib
-Imatinib
-Nilotinib
-Pazopanib
-Sorafenib
-Sunitinib

5

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

6

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)

7

DASTAINIB

-Also targets Src, a tyrosine kinase whose expression is unregulated in several types of cancer
----may be anti-metastatic in epithelial-derived tumors

8

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

9

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

10

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)

11

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%

12

When was CML discovered and what was the survival time?

-1900
-31 months

13

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

14

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

15

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

16

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

17

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

18

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

19

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)

20

What is Imatinib usually used for?

CML

21

What is Erlotinib/Gefitinib usually used for?

NSCLC

22

How well do we understand the genetic defect with Imatinib and Erlotinib/Gefitinib?

-Imatinib - Excellent
-Erlo/Gefit - Poor

23

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

24

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

25

Is there large scale success in treatment with Imatinib and Erlotinib/Gefitinib?

Imatinib - yes
Erlotinib/Gefitinib - Not really (fails more often than it works)