B.36. Cancer Chemotherapy V (small molecule signal transduction inhibitors) Flashcards
common characteristics of small-molecule TKI
- orally active
- once-daily dosing
- hepatic P450 metabolism
- act intracellularly
- act on mutated, constitutively active receptors that no longer rely on ligand binding
list the small molecules signal-transducing inhibitors
"-nib"--> TK inhibitor Imatinib Gefitinib Erlotinib Lapatinib Sunitinib Ibrutinib Crizotinib Trametinib (+Dabrafenib)
Bortezomib
Everolimus
Tretinoin-ATRA
what is Imatinib and what is its function?
Tyrosine Kinase inhibitor
binds to the BCR-ABL1 fusion gene and inhibits protein activity
what is Imatinib used for?
CML (positive Philadelphia chromosome translocation)
Gastrointestinal stromal tumors (+ for C-kit tyrosine kinase)
ALL
what are the side effects of Imatinib?
Diarrhea, nausea, vomiting Myalgia Fluid retention, peripheral edema CHF hepatotoxicity bone marrow suppression
what mutation causes resistance to Imatinib?
T315I mutation
what are Gefitinib and Erlotinib?
EGFR antagonists (1st generation) inhibits the TK domain of the receptor
indications for Gefitinib and Erlotinib?
non-small cell lung carcinoma
Erlo–> pancreatic cancer
side effects of Gefitinib, Erlotinib and Lapatinib
rash (acne-like)
Diarrhea
lapatinib–> cardiotoxicity
what is Lapatinib?
tyrosine kinase inhibitor
HER2/neu and EGFR pathways
when do we use Lapatinib?
Breast cancer (HER2 positive)
what is Sunitinib?
Receptor tyrosine kinase inhibitor
Antiangiogenic (PDGF-R, VEGF-R) –> limits vascularization to the tumor
when do we use Sunitinib?
Renal cell carcinoma
Imatinib resistant GIST (mutant c-kit)
side effects of Sunitinib
HYPERTENSION!
bleeding, nausea, diarrhea, vomiting
Side effects of Ibrutinib
most important:
hypertension
secondary malignancies–> non-melanoma skin cancers
also: URTI, sinusitis, myelosuppression
what is Ibrutinib?
TK inhibitor
binds to Bruton’s tyrosine kinase in B-cells and inhibit their activation
indications for Ibrutinib
CLL
Waldenström macroglobulinemia
mantle cell lymphoma
marginal zone lymphoma
what is Crizotinib?
ALK kinase inhibitor
ROS1 oncogene inhibitor
when do we give Crizotinib?
non-small cell lung carcinoma
when do we give Bortezombin?
multiple myeloma
when do we give the combination Dabrafenib +Trametinib?
malignant melanoma
side effects of Crizotinib
Nausea, vomiting, diarrhea
GI perforations
hepatotoxicity
side effects of Bortezomib?
peripheral neuropathy
thrombocytopenia
heart failure, hypotension
what is Bortezomib?
proteasome inhibitor
results in down-regulation of the NFᴋB signalling pathway
what is Dabrafenib?
BRAF inhibitor
what is Trametinib?
MEK inhibitor
what are the side effects of dabrafenib and trametinib?
skin problems
dabrafenib–> hyperkeratosis, hand-foot syndrome
trametinib–> acneiform dermatitis, rash
what is Everolimus?
mTOR inhibitor
Derivative of sirolimus
when is Everolimus used?
HER2 negative breast cancer
renal cell carcinoma
neuroendocrine tumors
liver, renal transplantation
side effects of Everolimus
stomatitis
infections
diarrhea
intestinal pulmonary disease
what is Tretinoin-ATRA( all-trans retinoic acid)?
Vitamin A derivative
what does Tretinoin-ATRA do
binds to retinoid X receptor (RXR) and retinoic acid receptor (RAR)
is a differentiating agent–> promotes differentiation of promyelocytes
when is Tretinoin used?
AML-M₃ type (acute promyelocytic leukemia)
*used as adjunct to chemotherapy
acne (topical agent)
side effects of Tretinoin
‘Differentiation syndrome’ (leukocyte maturation sy.)–> fever, ARDS, pleural and pericardial effusion, AKI
CNS symptoms
dry skin
osteomalacia
