B.33 Flashcards
Drugs used in cancer treatment V (Small molecule signal transduction inhibitors. Retinoids)
Imatinib,
Gefitinib,
Erlotinib,
Lapatinib,
Sunitinib,
Ibrutinib,
Crizotinib,
Bortezomib,
Dabrafenib+Trametinib,
Everolimus,
Tretionin
Imatinib
MOA: targets→ BCR-ABL, c-kit, PDGF-R tyrosine-kinases signaling inhibitor (→Inhibits the domain of BCR-ABL oncoprotein tyrosine-kinase, thus reducing the phosphorylation of the kinase by ATP);
Kinetics: adm. p.o., well absorbed, hepatic metabolism (CYP450), fecal elimination, terminal T1/2-16-18h;
IND: CML, GIST; SEs: Edema, Vomiting, Diarrhea, skin toxicity, cardiotoxicity
Gefitinib
MOA: EGFR and PDGF-R tyrosine-kinases signaling inhibitor;
Kinetics: hepatic metabolism (CYP3A4), terminal T1/2-46-49h;
IND: NSCLC (EGFR activated mutation);
SEs: itch, increased transaminase level, asthenia, blepharitis; Interactions: CYP3A4 interaction→ increased by phenytoin and phenobarbital, decreased by ketoconazole, erythromycin, grapefruit
Erlotinib
MOA: EGFR tyrosine-kinase signaling inhibitor;
Kinetics: Hepatic metabolism (CYP3A4), Terminal T1/2-36h;
IND: NSCLC (EGFR gene mutation and good effect is expected in case of wild type K-ras);
SEs: rashes, diarrhea, fatigue
Lapatinib
MOA: Targets EGFR1 and EGFR2 (HER2, ErBb2) tyrosine kinases;
IND: HER2 positive metastatic breast cc.;
Kinetics: can cross the BBB (treatment of CNS metastasis), Terminal T1/2-14h;
SEs: Cardiotoxicity, Severe diarrhea, Nausea
Sunitinib
MOA: targets- VEGF-R, PDGF-R, c-KIT (multityrosine kinases signaling inhibitor);
Kinetics: Hepatic metabolism (CYP3A4), Terminal T1/2-40-60h;
IND: GIST, Metastatic kidney cc, aggressive meningeoma;
SEs: Edema, vomiting, diarrhea, anemia, thrombocytopenia, HTN, Cardiomyopathy
Ibrutinib
MOA: Traget- BTK (Bruton-tyrosine-kinase) signaling inhibitor, irreversibly binding, inhibits the activity of the enzyme;
IND: CLL, Lymphocytic lymphoma, Waldenstrom-macroglobulinemia, second line treatment for rituximab resistance;
Kinetics: terminal T1/2-4-6h;
SEs: pneumonia, fever, infections, neutropenia, HTN, Tumor lysis syndrome
Crizotinib
MOA: Targets- ALK, HGFR and C-met tyrosine-kinases inhibitor;
IND: NSCLC (in case of ALK, ROS1 positivity);
Kinetics: terminal T1/2-42h;
SEs: nausea, vomiting, diarrhea, edema, chest pain, upper respiratory tract infections
Bortezomib
MOA: Target- reversible inhibitors of chymotrypsin type 26S proteasome activity (when the proteasome doesn’t work a large number of gene mutation favor the accumulation of defective proteins that cause cell death);
IND: Myeloma multiplex;
SEs: hyponatremia, hypokalemia, fatigue, neurotoxicity, congestive HF, tumor lysis syndrome:
Dabrafenib +Trametinib
MOA: Targets
- Dabrafenib: BRAF serine/threonine kinase inhibitor,
-Trametinib: MEK1/2 inhibitor;
IND: metastatic melanoma (should be validated BRAFV600E mutation-positive test before starting treatment);
SEs: hyperkeratosis, headache, fever, joint pain, hand-foot syndrome
Everolimus
MOA: mTOR serine/threonine-kinase signaling inhibitor;
IND: HER-2 negative breast cc, Neuroendocrine tumor with advanced pancreatic origin (pNET), Advanced kidney cc, Astrocytoma, Sclerosis tuberosa;
SEs: anemia, thrombocytopenia, stomatitis, nausea, vomiting, anorexia, change in taste, nosebleed, sore throat, headache
Tretinoin
MOA: exact mechanism not fully understood →Transisomer of the synthetic retinol (it is believed that it binds and activates 2 types of nuclear receptors - retinoic acid receptors α, β and γ →gene transcription regulation. and retinoid X receptors →promoting epidermal proliferation) ;
IND: Acute promyelocytic leukemia;
SEs: headache, depression, dry skin, hair loss, vision loss, myalgia, leukocytosis, thrombosis, teratogenic; Contra-IND: Pregnancy
Terminal half life
the time required to divide the plasma cc by 2 after reaching pseudo-equilibrium, and not the time required to eliminate half the administered dose (which is the T1/2)
How low molecular weight inhibitors work?
The molecular targets of signaling drugs are the activated protooncogenes and tyrosine or Serine/threonine-kinases that are continuously activated due to the inactivation of tumor suppressor genes
BCR-ABL tyrosine kinase inhibitors
Imatinib, Nilotinib, Dasatinib, Regorafenib
