B.34 Flashcards
Drugs used in cancer treatment VI (Large molecule signal transduction inhibitors. Immunostimulant anticancer drugs.)
Large molecule signal transduction inhibitors: Trastuzumab (-emtansine), Panitumumab, Rituximab, Bevacizumab
Immunostimulant anticancer drugs: α-IFN, Aldesleukin, Pembrolizumab
Trastuzumab (-emtansine)
MOA: Humanized Anti HER-2 Ab (binds specifically to the extracellular domain of HER-2);
Kinetics: CANNOT cross the BBB;
IND: HER2-positive metastatic breast cc, HER2-positive metastatic gastric and gastroesophageal junction adenocarcinoma;
SEs: Cardiotoxicity (HF- In combination with anthracycline the SEs are more pronounced!), Teratogenic (contraception is required during treatment and 6 months after treatment), CNS and GI symptoms, skin rashes, Flu-like symptoms;
Trastuzumab-emtansine (T-DM1)
MOA: Antibody drug conjugate (ADC) group agent → Emtansine is covalently linked to Trastuzumab (DM1, cytotoxic drug) →receptor-mediated internalization into the cells→catabolics containing DM-1 are released→binding to tubulin→ mitosis arrest→cell death);
IND: HER2-positive metastatic breast cc (after previous therapy)
Panitumumab
MOA: Human anti EGFR Ab → binds specifically to EGFR, HER1, c-ErbB1;
IND: Metastatic colorectal cc (KRAS wild type), squamous cell carcinoma of the head and neck;
SEs: CNS (fatigue, malaise, peripheral sensory neuropathy), skin symotms (e.g. acne-like rash), GI symptoms, Myelosuppressio
Rituximab
MOA: Chimeric mAb against B cells (it kills both normal and malignant B cells with CD20 on their surface and develops a new, healthy population from lymphoid stem cells;
IND: CD20-positive CLL, CD20-positive NHL, Wegener’s Granulomatosis, RA, Microscopic polyangitis (MPA); SEs: infusion reaction (severe and even fatal), mucocutaneous rections (severe and even fatal), HBV reactivation (HBV screening required in all patients), PML (progressive multifocal leukoencephalopathy (reactivation of JC virus), infections
Bevacizumab
MOA: Binds to VEGF and neutralizes it (angiogenesis inhibitor);
IND: Metastatic colorectal cc (1st/2nd line, in combination), Recurrent glioblastoma, NSCLC, Epithelial ovarian/tubal/primary peritoneal cc, metastatic renal cell cc,
(off lable: age-related macular degeneration, diabetic macular edema, endometrial cc, glioblastoma…);
SEs: GI perforation (even fatal), Wound healing and surgical complications!, Bleeding & hemoptysis (severe and even fatal), GI (nausea) and CNS symptoms, Decreased blood cell count, infections, muscle pain, proteinuria, UTIs
α-IFN
MOA: Binds to specific receptor on the cell membrane→
1. induction of transcription,
2. Inhibition of cell growth, Influencing cell differentiation, immune cell activation, TH1 immune response,
3. Influencing oncogene expression, modifying cell surface antigen expression,
4. Increasing macrophage phagocytic function and lymphocyte cytotoxicity;
IND: AIDS-associated Kaposi’s sarcoma, Follicular NHL, Hairy cell leukemia, Melanoma, chronic HBV/HCV, Condyloma accuminatum (HPV);
SEs: CNS/GI/ BM suppression, Musculoskeletal pain, Flu-like symptoms, Fever, Rashes, Alopecia
Aldesleukin
MOA: recombinant IL-2 →proliferation, differentiation and recruitment of T and B cells, NK cells and thymocytes;
IND: metastatic melanoma, Metastatic renal cell cc; Kinetics: ROA→high-dose intensive i.v therapy, low-dose s.c. therapy, intratumoral injection;
SEs: Flu-like symptoms, Cardiovascular (hypotension, edema, tachycardia), Capillary leak syndrome (mainly in lung and brain →ICU supervision required!), Antibody formation (~70%)
Pembrolizumab
MOA: Humanized Anti-PD-1 Ab (Immune checkpoint inhibitor) [→ T-cell inhibition in tumor cells: PD-1 immune checkpoint inhibits effector T cells in peripheral tissues, PD-1L (ligand) is frequently expressed in tumor cells → inhibits the anti-tumor immune response], The binding of Pembrolizumab to PD-1 prevents this inhibitory pathway, causing a physiological shift towards immune reactivity and enhancing tumor immunosurveillance and anti-tumor immune response;
IND: Melanoma, NSCLC, cHL;
SEs: autoimmune diseases (colitis, skin reactions, immunotoxic endocrine disorders, Hepatitis, Cardiotoxicity (rare but serious SE, occurs in ~1% of patients, can be fatal, mainly myocarditis)
KRAS wild type
ells with KRAS mutations are resistant to EGFR inhibition (New KRAS G12C mutation targeting therapeutic agent: Lumakras (sotorasib) with promising results in NSCLC, CRC, pancreatic cc), FOLFIRI combination: [irinotecan, fluorouracil, leucovorine]
How do tumor cells survive?
- Angiogenesis
* VEGF-Rs
* Angiogenesis is a rate-determining step in many pathological processes
* VEGF-inhibition effect - Immuno-editing
-Elimination
-Equilibrium
-Getting away
VEGF-Rs
VEGF-R1, VEGF-R2, VEGF-R3
- They can be membrane bound and soluble
- active role in the induction, maintenance and growth of vascular endothelial cells
→Tumor vasculature: permeable and irregular structure compared to normal capillaries
- VEGF-inhibition effect
- Inhibition of endothelial proliferation in tumor tissue
→ reduction in tumor microvasculature system- Normalization of the vascular system
→ Reduced :vascular permeability improved tumor blood flow and reduced tumor interstitial pressure increased targeting of chemotherapeutic agents - Edema reduction (ICP!)
- Normalization of the vascular system
Elimination
T, B, NK cells and macrophages have an anti-tumor effect
Cytokine mediated (IFN-α, IFN-γ, IL-12)
Equilibrium
balance between the immune-mediated tumor suppression and the rare, resistant malignant clones
