cytostatic cancer chemotherapy: hormonal agents, small molecule signal transduction inhibitors, large molecule signal transduction inhibitors (B35-37) Flashcards
Cytostatics
I. Small molecular weight:
Non-receptor tyrosine kinase inhibitors: cytostatics Imatinib Ibrutinib Crizotinib dabrafenib + trametinib
Tyrosine kinase receptor inhibitors: gefitinib erlotinib lapatinib (sorafenib) sunitinib
Proteasome inhibitor:
bortezomib
mTOR inhibitor:
everolimus
Vitamine analogs Retinoids:
tretinoin
(bexaroten)
II. Biologics (antibodies, immune toxins, cytokines):
trastuzumab - Tyrosine kinase receptor inhib
trastuzumab-emtansin - Cytotoxic, mitotic arrest
(cetuximab) - Tyrosine kinase receptorinhib
panitumumab - Tyrosine kinase receptor inhib
rituximab - Anti CD-20
bevacizumab - Anti VEGF
(ipilimumab) - Checkpoint inhibitor
(nivolumab) - Checkpoint inhibitor
pembrolizumab - Checkpoint inhibitor
alpha-interferon
aldesleukin - Rekomb. IL2
III. Hormonal drugs:
Tamoxifen Fulvestrant (exemestane) anastrozole (buserelin) degarelix bicalutamide
Targeted therapy
targeted drugs zero in on some of the changes that make cancer cells different. They target specific areas of the cancer cell that allow the cell to grow faster and abnormally. There are many different targets on cancer cells and many drugs that have been developed to attack them
In general:
- block or turn off chemical signals that tell the cancer cell to grow and divide
- change proteins within the cancer cells so the cells die
- stop making new blood vessels to feed the cancer cells
- trigger your immune system to kill the cancer cells
- carry a toxin to the cancer cell to kill it, but not normal cell
types of targeted Therapy:
- nibs- small molecule kinase inhibitors
(nib = inhibit)
- a kinase is an enzyme that transfers a phosphate group from ATP to a specific molecule (phosphorylation)
- Kinases are critical in metabolism, cell singling, protein regulation, cellular transport, secretory processes and many other cellular pathways
- many different kinds of kinases: Protein kinases, lipid kinases, carbohydrate kinases, nucleoside kinases+ many more
- nabs- nanoparticle, albumin-bound
- allows for non-toxic delivery of hydrophobic therapeuti compounds
- exploits the natural properties of albumin. Albumin reversibly binds to and transports wide range of molecules from the bloodstream to cells
- once the nab.drug comic enter the interstitial space, the drug “payload” is released from the albumin
- The cytotoxic drug then diffuses into the tumor cells where it induces apoptosis
- Potential mechanism of toxicity: the tumor vasculature is highly permeable to albumin (albumin activated gp-60 pathway)
- mibs- proteasome inhibitor
- the proteasome is responsible for the digestion of proteins inside the cell
- if proteasome function is blocked, the build-up of these proteins triggers apoptosis
- mAbs- Monoclonal Antibodies
- Direct signaling induced death of cancer cells (e.g. hercep@n and rituximab).
- Inhibit angiogenesis (e.g. bevacizumab)
- Block inhibitory signals thereby resulting in a stronger anti-tumor T cell response (e.g. ipilimumab and nivolumab)
- Deliver radioisotopes (e.g. 131I tositumomab)
- Deliver highly potent toxic drugs directly to cancer cells (trastuzumab emtansine)
- Retarget immune cells towards cancer cells with special mAb that connects the two (e.g. blinatumomab)
- CAR T-cells
- Immune checkpoint inhibitors are a hot area of clinical research, they block the signal that would have prevented activated T-cells from attacking the cancer
Tyrosine kinase
- enzyme that can transfer a phosphate group from ATP to a protein in a cell
- „on-off” switch (mutation stucked in on state)
- receptor tyrosine kinases (RTKs)
- 20 subfamilies
- extracellular domain + transmembrane domain + intracellular catalytic domain
- Cytoplasmic/non-receptor
- 32 cytoplasmic protein tyrosine kinases
- cytosolic enzymes
- multiple roles; critical components in the regulation of the immune system
-momab
Mouse mAB
Blinatumomab
(not evaluated in MS)
-ximab
Chimeric mAB
Retuximab
Cetuximab
Infliximab
-zumab
humanised mAB
Trastuzumab
Bevacizumab
Pembrolizumab
-mumab
Human mAB
Ipilumumab
Nivolumab
Characteristics ob -mabs
size and structure: large complex molecules with structure affected by manufacturing process
Chemical class: protein/peptide
Production: Cell culture
Generic: Biosimilar
Site of action: Cell membrane receptor
Specificity: Specific
Stability: sensitive to external conditions (heat, microbial contamination)
Route of administration: Subcutaneous or intravenous
Half-life: longer
Immunogenecity:
Drug interaction:
characteristics of -mibs and -nibs
size and structure: single molecule with exact chemical structure
Chemical class: often inorganic
Production: chemical synthesis
Generic: identical copy
Site of action: intracellular
Specificity: usually non-specific
Stability: generally stable
Route of administration: various including oral
Half-life: shorter
Immunogenecity: usually non-immunogenic
Drug interaction: more common
Tyrosine-kinase inhibitors
Receptor tyrosine kinase:
I. ErbB:
- HER1/EGFR
a) ERLOTINIB
b) GEFITINIB
(Brigatinib,) (Olmutinib, ) (Osimertinib,) (Rociletinib, ) (Vandetanib )
- HER1/EGFR and HER2/neu
a) LAPATINIB
(Neratinib)
(Afatinib)
II. RTK class III
- C-kit and PDGFR
a) SUNITINIB
(Axitinib,) (Masitinib), (Pazopanib,) (Sorafenib,) (Toceranib,) (Regorafenib)
- FLT3
(Lestaurtinib)
III. VEGFR
a) SUNITINIB
(Axitinib ) (Cediranib ) (Lenvatinib) (Nintedanib ) (Pazopanib ) (Regorafenib) (Semaxanib) (Sorafenib ) (Tivozanib) (Toceranib ) (Vandetanib)
RET inhibitors:
(Vandetanib, Entrectinib)
c-MET inhibitor:
( Cabozantinib)
- Orally active
- Once-daily dosing
- Hepatic P450 metabolism
- Act intracellularly
- Act on mutated, constitutively active receptors that
no longer rely on ligand binding
HER1/EGFR inhibitors
gefitinib, erlotinib
HER1/EGFR and HER2/neu inhibitor
lapatinib
gefitinib, erlotinib
HER1/EGFR inhibitors (ErbB)
- EGFR antagonists
- Inhibit the tyrosine kinase domain
of the receptor
- Only active in presence of EGFR receptor mutations
- inhibition of tumor angiogenesis
- Ind: NSCLC (erlotinib for pancreas as well)
- SE: skin rash, diarrhoea, increased transaminases
lapatinib
HER1/EGFR and HER2/neu
(ErbB)
- Ind: breast cancer (HER+, in case of trastuzumab rezistence, CNS penetration – in case of metastasis)
- SE: cardiotoxicity, GI
RTK class III C-kit and PDGFR inhibitor
sunitinib
sunitinib
RTK class III C-kit and PDGFR
- VEGFR is included also in mechanism of action
-indication:
kidney, gastrointestinal stromal tumors (GIST), neuroend. pancreas
- SE:
VEGFR inhibition high blood pressure
fatigue, diarrhea, nausea, anorexia, a yellow skin discoloration, hand-foot skin reaction, and stomatitis
Serious adverse events occur in ≤10%
targets numerous receptors including c-kit, VEGFR1-3, PDGFR-alpha, PDGFR-beta, FLT3, CSF-1R, and Rearranged during Transfection (RET).
vese, GIST, neuroend. pancreas
multitargeted tyrosine kinase inhibitors (e.g.)
Sunitinib
targets numerous receptors including c-kit, VEGFR1-3, PDGFR-alpha, PDGFR-beta, FLT3, CSF-1R, and Rearranged during Transfection (RET).
vese, GIST, neuroend. pancreas
(Sorafenib) (not on the list)
inhibits VEGFR2, fms-like tyrosine kinase 3 (FLT3), PDGFR, and fibroblast growth factor receptor (FGFR)-1.
vese, máj, pajzsmirigy
(pazopanib): (not on the list)
VEGFR is included also in mechanism of action
ind.: kidney, soft-tissue sarcoma
regorafenib:
VEGFR is included also in mechanism of action
ind.: CRC (colorectal cancer), GIST
targets VEGFR1-3, PDGFR alpha and beta, FGFR1 and 3, c-kit, and other tyrosine kinases.
kidney, soft tissue sarcoma
Non-receptor tyrosine kinase
bcr-abl:
1. IMATINIB
(Dasatinib)
(Nilotinib)
(Ponatinib)
(Radotinib)
Src:
(Bosutinib,)
(Dasatinib)
Janus kinase: (Lestaurtinib ) (Momelotinib) (Ruxolitinib) (Pacritinib)
MAP2K (Cobimetinib) (Selumetinib) (Trametinib) (Binimetinib)
DABRAFENIB + TRAMETINIB
EML4-ALK
( Alectinib)
(Brigatinib)
(Ceritinib)
- CRIZOTINIB
Bruton’s
- IBRUTINIB
- Orally active
- Once-daily dosing
- Hepatic P450 metabolism
- Act intracellularly
- Act on mutated, constitutively active receptors that
no longer rely on ligand binding
Philadelphia chromosome:
- specific genetic abnormality in chromosome 22 of leukemia cancer cells (CML) – 90% <
- also found in acute lymphoblastic leukemia (ALL) and occasionally in acute myelogenous leukemia (AML) as well as mixed-phenotype acute leukemia (MPAL)
- contains a fusion gene called BCR-ABL1
- coding a hybrid protein for a tyrosine kinase that is always „on”
- affects multiple signaling pathway -> JAK/STAT; Ras/MAPK/ERK Pathway
translocation t(9:22)
BCL-ABL fusion protein
Imatinib
Non-receptor tyrosine kinase
Bcr-Abl tyrosine-kinase inhibitors:
- the first Bcr-Abl tyrosine kinase inhibitor
- (example of high-throughput screening)
MOA:
- disrupts the ATP phosphate binding site to block the catalytic activity of the enzyme
- also ckit and PDGF-R inhibitory effect
Ind.:
- Ph+ CML and ALL,
- Gastrointestinal stromal tumors (GIST)
Pk:
CYP3A4 metabolizes
SE:
- fluid retention
- gastrointestinal bleeding
- bone marrow suppression
- liver problems
- heart failure
- common: GI, muscle pain, headache, and rash
resistance:
1. Bcr-Abl dependent:
over expression; point mutations
- T315I mutation -> resistance to all approved Bcr-Abl inhibitors (kiv. ponatinib)
- Mutations in the P-loop
- Bcr-Abl non-dependent:
- efflux by P-glycoproteins
- organic cation transporter (OCT1): low expression/polymorphisms
- Alternative signaling pathway activation - Src
- second generation
crizotinib
Non-receptor tyrosine kinase
- late stage ALK-positive NSCLC
SE:
- cardiovasc (edema)
- neuropathy
- GI
- Neutropenia,
- lymphocytopenia
- Visual disturbance
- Upper respiratory tract infection
- fever
((( alectinib (FDA, 2017: first choice)
ALK-RET inhibitor
ALK-positive, metastatic non-small cell lung cancer
certinib, brigatinib
ALK-positive metastatic non-small cell lung cancer (NSCLC))))
