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))))
Ibrutinib
Non-receptor tyrosine kinase
- Bruton’s tyrosine kinase (BTK)
- crucial role in B cell maturation as well as mast cell activation
- binds permanently to BTK
Ind.:
- B cell cancers like mantle cell lymphoma,
- chronic lymphocytic leukemia, and
- Waldenström’s macroglobulinemia
SE:
- lot of adverse effects
- pneumonia, upper respiratory tract infection, sinusitis
- skin infection,
- low neutrophil count,
- low platelet counts
- headache,
- bleeding,
- bruising,
- diarrhea, vomiting, nausea,
- constipation
- inflammation of mouth and lips
- rash
- joint pain, muscle spasms, musculoskeletal pain
- fever, and edema
(((Acalabrutinib
more potent and selective (fewer side-effects)
2nd choice )))
dabrafenib+ trametinib
ERK signaling pathway is involved in both physiological and pathological cell proliferation
Dabrafenib: - BRAF inhibitor
Tramefinib: MEK inhibitor
MEK1 and MEK2 inhibitor
ind.: BRAF-mutated melanoma (+ dabrafenib)
- Orally active
- Once-daily dosing
- Hepatic P450 metabolism
- Act intracellularly
- Act on mutated, constitutively active receptors that
no longer rely on ligand binding
mTOR
- mammalian target of rapamycin (mTOR): serine/threonine-specific protein kinase
- regulates cellular metabolism, growth, and proliferation - PI3K/AKT/mTOR pathway
- forms two distinct multiprotein complexes: mTORC1 and mTORC2 -> separate network of protein partners
- enhanced by (e.g.): EGF, shh (sonic hedgehog), IGF-1, insulin …
- many human tumors occur because of dysregulation of mTOR signaling
everolismus
1st generation mTOR inhibitors:
inhibition of mTORC1
bind to FKBP-12 -> form a complex which inhibits mTOR signaling -> halting the cell cycle at the G1 phase
pharmacokinetics:
better than sirolimus
Ind.:
- HER2-negative breast cancer,
- advanced, metastatic or unresectable progressive pancreatic neuroendocrine tumors (PNET),
- GI or
- lung neuroendocrine tumors,
- RCC
- liver-, renal transplantation
sirolimus (rapamycin), (temsirolimus):
Ind.:
renal cell carcinoma (RCC)
SE:
nausea,
stomatitis,
and anemia
Bortezomib
Proteasome inhibitors:
- prevention of degradation of pro-apoptotic factors such as the p53 protein
- multiple myeloma
Bortezomib- (inj.): usually combined with dexamethasone
MOA:
- contains Boron atom -> binds the catalytic site of the 26S proteasome
Ind.:
- multiple myeloma;
- mantle cell lymphoma
Off label:
- Antibody-mediated rejection in cardiac transplantation (treatment);
- Cutaneous T-cell lymphomas:
- mycosis fungoides;
- Follicular lymphoma;
- Peripheral T-cell lymphoma;
- Systemic light-chain amyloidosis;
- Waldenström macroglobulinemia
SE:
- peripheral neuropathy
- myelosuppression
- CNS,
- GI
(((Ixazomib (per os): + lenalidomide + dexamethasone
Carfilzomib: after received at least two prior therapies)))
tretinoin
Vitamin analogs – Retinoids
- tipically they are used in dermatology (severe acne, psoriasis) – 3 generations
- taken orally
Indication:
- Acute promyelocytic leukemia - remission induction
- bind one or more nuclear receptors and decreases proliferation
SE: very common: 1. Peripheral edema, 2. chest discomfort, 3. arrythmia 4. headache (86%), 5. Ostealgia 6. xeroderma, 7. Hemorrhage 8. infections 9. Increased liver enzymes 10. fever
- All retinoids are teratogenic!!!! -> two reliable forms of contraception should be used
Vitamin analogs- retinoids
- tipically they are used in dermatology (severe acne, psoriasis) – 3 generations
- First generation:
(retinol),
(retinal),
TRETINOIN =retinoic acid, (isotretinoin),
((alitretinoin - (locally):
Ind.: skin lesions in AIDS-related Kaposi’s sarcoma
not indicated when systemic therapy is required))
- Second generation: (etretinate) and its metabolite (acitretin)
- Third generation: (adapalene),
((bexarotene - (systemic):
Ind.: cutaneous T cell lymphoma (CTCL)
in patients who are refractory to at least one prior systemic therapy
also used for topical treatment of cutaneous lesions (not tolerated other therapies))
(tazarotene)
Proteasome inhibitor
Bortezomib
mTOR inhibitor
everolimus
sirolimus
trastuzumab (-emtansin)
HER2 (EGFR2, CD340, Erbb2) antibodies:
Receptor tyrosine kinase:
ErbB:
HER2/neu
Trastuzumab:
- binds to the extracellular domain of HER-2
- Tyrosine kinase receptor inhib
Ind.:
- HER2-overexpressing metastatic breast cancer
- HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma
SE:
- trastuzumab administration can result in cardiac failure! - anthracycline-containing chemotherapy regimens!
- >Evaluate left ventricular function in all patients - in women: contraception while taking trastuzumab, and for at least six months afterwards!
- CNS,
- GI
- skin rash
- flu like symptoms
Trastuzumab-emtansine (T-DM1):
- antibody-drug conjugate: trastuzumab covalently linked to the cytotoxic agent emtansine (DM1)
- > undergoes receptor-mediated internalization into cells
- >DM1-containing catabolites are released
- > subsequently bind tubulin to cause mitotic arrest and cell death
- > undergoes receptor-mediated internalization into cells
-Cytotoxic, mitotic arrest
Ind.:
HER2-positive, metastatic breast cancer (after prior therapy)
panitumumab
EGFR antibodies:
Receptor tyrosine kinase:
ErbB:
HER1/EGFR
- binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1)
- cells with KRAS mutations appear to be unaffected by EGFR inhibition
- diagnostic immunohistochemistry assay („misleading biomarker”?)
Ind.:
- metastatic colorectal cancer (KRAS wild-type)
- > in combination with FOLFIRI [irinotecan, fluorouracil, and leucovorin] as first-line treatment - squamous cell cancer of the head and neck
SE:
- CNS: Fatigue, malaise, pain, peripheral sensory neuropathy
- Dermatologic symptoms (e.g. acne like rash)!!
- GI
- myelosuppression
((((Pertuzumab:
inhibits the dimerization of HER2 with other HER receptors
Ind.:
Adjuvant treatment of HER2-positive breast cancer
(HER2)-positive metastatic breast cancer: in combination with trastuzumab and docetaxel
Pertuzumab can result in cardiac failure)))
rituximab
Anti CD20 antibodies:
B-lymphocyte antigen CD20:
- expressed on the surface of all B-cells
- absent on terminally differentiated plasma cells
- no known natural ligand (acts as a Ca channel?)
- agents in the treatment of all
1. B cell lymphomas,
2. leukemias, and
3. B cell-mediated autoimmune diseases
Rituximab:
- destroys both normal and malignant B cells that have CD20 on their surfaces -> new population of healthy B cells to develop from lymphoid stem cells
Ind.:
- CD20-positive chronic lymphocytic leukemia (CLL)
- CD20-positive non-Hodgkin lymphomas (NHL)
- granulomatosis with polyangiitis (GPA; Wegener granulomatosis)
- rheumatoid arthritis (in combination with methotrexate)
- microscopic polyangiitis (MPA)
SE:
- serious, including fatal, infusion reactions
- Severe, including fatal, mucocutaneous reactions can occur
- Hepatitis B virus (HBV) reactivation
- > Screen all patients for HBV infection - Progressive multifocal leukoencephalopathy (PML)
- > progressive damage (-pathy) or inflammation of the white matter (leuko-) of the brain (-encephalo-) at multiple locations (multifocal) – John Cunningham virus - Infections
Rituximab and hyaluronidase (subcutaneous adm.)
bevacizumab
Vascular endothelial growth factor A (VEGF-A) antibodies:
- main, dominant inducer to the growth of blood vessels
wound healing, tumor angiogenesis, diabetic retinopathy, and age-related macular degeneration
Bevacizumab
MOA:
binds to, and neutralizes VEGF
Ind.:
- persistent, recurrent, or metastatic cervical cancer (combination)
- First- or second-line treatment of metastatic colorectal cancer (CRC) (comb.)
- recurrent glioblastoma
- non-small cell lung cancer (NSCLC)
- epithelial ovarian,
- fallopian tube, or
- primary peritoneal cancer
- metastatic renal cell carcinoma (RCC) (comb. with IFα)
Off label:
- Age-related macular degeneration,
- Diabetic macular edema, 3. Endometrial cancer,
- Glioblastoma …
SE:
- wide variety of common side effects
- incidence of GI perforations (some fatal) increased !
- wound healing and surgical complications!
- Withhold bevacizumab products at least 28 days prior to elective surgery!
- Do not administer bevacizumab products for at least 28 days after surgery!
- Severe or fatal hemorrhage, including hemoptysis!
- Do not administer to patients with a recent history of hemoptysis
- GI (nausea 72%),
- CNS
- lowered blood cell count
Infection (55%; serious: 7% to 14%)
- muscular pain
- Increased serum creatinine
- proteinuria,
- urinary tract infection
- hypertension
pembrolizumab
THERAPEUTIC APPROACHES:
Checkpoint inhibitors
PD-1 and PD ligand 1/2 (PDL1 on tumors):
antibodies inhibiting PD-1 (pembrolizumab, nivolumab)
- Immunomodulator
(check-point protein modulator) - Antibody binds PD-1 receptor of lymphocytes (programmed cell death protein 1) → T-cell activated (prevent co-inhibitory signal)
- Humanized monoclonal Ab (IgG4 isotype)
- Melanoma
- Non-small cell lung carcinoma
- Injection site reaction
- Pneumonitis
- Inflammation of endocrine glands
cetuximab
not on the list
Receptor tyrosine kinase:
ErbB:
HER1/EGFR
binds specifically to the epidermal growth factor receptor (EGFR, HER1, c-ErbB-1)
cells with KRAS mutations appear to be unaffected by EGFR inhibition
diagnostic immunohistochemistry assay („misleading biomarker”?)
Ind.:
metastatic colorectal cancer (KRAS wild-type)
in combination with FOLFIRI [irinotecan, fluorouracil, and leucovorin] as first-line treatment
squamous cell cancer of the head and neck
SE:
CNS: Fatigue, malaise, pain, peripheral sensory neuropathy
Dermatologic symptoms (e.g. acne like rash)
GI
myelosuppr
ipilimumab
not on the list
THERAPEUTIC APPROACHES:
Checkpoint inhibitors
CTLA-4 (turns of cytotoxic reaction)
anti-CTLA-4 antibody : ipilimumab, Tremelimumab
- immunstimulator
Ind.: metastatic colorectal cancer (CRC) melanoma renal cell carcinoma Usually combined with nivolumab: selectively inhibits programmed cell death-1 (PD-1) Ind.: CRC, melanoma, renal cell carcinoma squamous cell carcinoma of the head and neck hepatocellular carcinoma (HCC) classical Hodgkin lymphoma (cHL) NSCLC, SCLC urothelial carcinoma
SE:
severe autoimmun syndromes: immune-mediated reactions may involve any organ system
most common: enterocolitis, hepatitis, dermatitis (including toxic epidermal necrolysis), neuropathy, and endocrinopathy (thyroid, hypophysitis, type 1 diabetes)
systemic high-dose corticosteroid therapy (IFα)
nivolumab
not on the list
THERAPEUTIC APPROACHES:
Checkpoint inhibitors
antibodies inhibiting PD-1 (pembrolizumab, nivolumab)
aldesleukin
IL2:
Aldesleukin: recombinant interleukin-2
- promotes proliferation, differentiation, and recruitment of T and B cells, natural killer (NK) cells, and thymocytes
Ind.:
- metastatic melanoma
- metastatic renal cell cancer
SE:
- cardiovascular! (hypotension, edema, tachycardia…)
- capillary leak syndrome (CLS)
- > intensive care facility and specialists skilled in cardiopulmonary or intensive care medicine must be available - Antibody development (66% to 74%)
Checkpoint inhibitors
PD-1 and PD ligand 1/2 (PDL1 on tumors):
antibodies inhibiting PD-1:
Pembrolizumab
(Nivolumab)
PD-L1
(atezolizumab, avelumab, durvalumab)
- anti-CTLA-4 antibody
not on the list
ipilimumab, Tremelimumab
CTLA-4 (turns of cytotoxic reaction)
Checkpoint inhibitors
PD-1 and PD ligand 1/2 (PDL1 on tumors)
CTLA-4
In general, PD-1 and PD-L1/L2 are upregulated in the context of pro-effector cytokines such as IL-12 and IFN gamma, highlighting their role as a physiologic brake on unrestrained cytotoxic T effector function [43,44]. There are additional binding partners outside of the PD-1:PD-L1 axis; for example, PD-L1 has also been shown to inhibit CD80 [45], suggesting layers of interaction between Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), PD-1, and other pathways; these require further research to elucidate the context-dependent roles of each pathway in regulating T effector cell function.
CTLA-4 was discovered in 1987 and implicated as a negative regulator of T cell activation in the mid-1990s [46-48]. CTLA-4 exerts its effect when it is present on the cell surface of CD4+ and CD8+ T lymphocytes, where it has higher affinity for the costimulatory receptors CD80 and CD86 (B7-1 and B7-2) on antigen-presenting cells (APCs) than the T cell costimulatory receptor CD28 (figure 5) [49]. The expression of CTLA-4 is upregulated by the degree of T cell receptor (TCR) activation and cytokines such as IL-12 and IFN gamma, forming a feedback inhibition loop on activated T effector cells. As a result, CTLA-4 can be broadly considered a physiologic “brake” on the CD4+ and CD8+ T cell activation that is triggered by APCs.
recombinant interleukin-2
Aldesleukin
INFα
- Binds to a specific receptor on the cell membrane
- induction of gene transcription
- Inhibits cellular growth, alters the state of cellular differentiation
- interferes with oncogene expression, alters cell surface antigen expression
- increases phagocytic activity of macrophages, and augments cytotoxicity of lymphocytes for target cells
Ind.: 1. AIDS-related Kaposi sarcoma 2. follicular non-Hodgkin lymphoma 3. hairy cell leukemia 4.malignant melanoma 5. chronic hepatitis B 6.chronic hepatitis C 7. condylomata acuminata (HPV) renal cell carcinoma?
SE: - CNS, - GI, - bone marrow suppr. - musculoskeletal pain - Flu-like symptoms (children: 100%) - fever - skin rash, alopecia …
FEHLT:
tamoxifen anastrozole goserelin degarelix bicalutamide prednisolone octreotide
SPÄTER EINFÜGEN
Hormonal anticancer agents
tamoxifen anastrozole goserelin degarelix bicalutamide prednisolone octreotide
Common side effects of hormonal therapy:
- Vasomotor symptoms (sweating, hot flushes) - Musculoskeletal presentations
- Metabolic alterations - Increased risk of venous thromboembolism
cytostatic, not cytotoxic
tamoxifen
- Selective estrogen receptor modulator (SERM)
- Estrogen antagonist action → breast, CNS, uterus
- Estrogen agonist action → liver, bone
- Breast cancer (estrogen receptor positive disease)
- Used as prophylaxis in women at high risk for breast cancer
- Nausea, vomiting
- Hot flushes
- Vaginal bleeding
- Thromboembolic events
- Endometrial hyperplasia and neoplasia (partial
agonist in the endometrium)
anastrozole
- Aromatase inhibitor
Antiestrogen- synthesis inhibitor
- Breast cancer (advanced disease)
- Nausea, vomiting, diarrhea
- Hot flushes
- Musculoskeletal disorders (joint + bone pains)
- Altered bone mineral density- reduced
goserelin
- GnRH agonist
- Synthetic peptide
- Continuous administration of GnRH
agonists → inhibits the release of FSH and LH → both androgen and estrogen syntheses are reduced - Prostate cancer
- Breast cancer
- Leiomyoma
- Endometriosis
- Headaches, nausea
- Injection site reaction
- Symptoms of hypogonadism with continuous
treatment (impotence in male)
Synthetic peptide with GnRH agonist activity
- Parenteral
Long-acting
- Continuous administration of GnRH agonists suppresses gonadotropin secretion and thereby inhibits ovarian production of estrogens and progesterone
- Ovarian suppression in women undergoing controlled ovulation induction
- Ovarian suppression in endometriosis, leiomyoma
- Central precocious puberty
- Prostate cancer
- Side effects: headache, nausea, injection site reaction,
symptoms of hypogonadism with continuous treatment
degarelix
- GnRH antagonist
- GnRH receptor inhibition → altered
release FSH and LH → testosterone synthesis ↓ - Prostate cancer
- Nausea, vomiting
- Headaches
GnRH antagonists
- Parenteral
- Controlled ovarian stimulation (suppress endogenous LH and FSH)
- Side effects: nausea, headache
bicalutamide
- Androgen receptor inhibitor
- Prostate cancer
- Gynecomastia
- Hot flushes
- Impotence
- Hepatoxicity
- Competitive inhibitor of androgen receptors
- Oral
- Prostate cancer
- Precocious puberty
- Side effects: gynecomastia, hot flushes, impotence,
hepatoxicity
prednisolone
- Activation of glucocorticoid receptors alters gene transcription
Intermediate (12-36 h’)
Pharmacokinetic:
- High bioavailability (good oral absorption)
- Transport in blood: 90% corticosteroid-binding globulin (CBG),
5-10% free form
- T1/2 60-90 min’
- Metabolism: 80% hepatic, 20% renal and/or other
MOA:
- Leukocyte migration ↓
- Lysosomal membrane stabilization → phagocytosis ↓
- Capillary permeability ↓
- PLA2 inhibition → prostaglandins and leukotrienes ↓
- COX-2 expression ↓
- Platelet-activating factor (PAF) ↓
- Interleukins (ex. IL-2) ↓
- Inhibition of NF-κB pathway (TNF-α, IL-2 ↓)
- Induction of apoptosis in lymphocytes through activation of caspase enzymes
- Acute leukemias
- Hodgkin’s lymphoma
- Non-Hodgkin’s lymphoma
- Iatrogenic Cushing syndrome
octreotide
- Somatostatin (GHIH) analogue - GH anatagonist
- Inhibit the release of GH, insulin,
glucagon, gastrin
- Endocrine tumors → carcinoid, gastrinoma, glucagonoma, insulinoma, VIPoma
- GI disturbances (constipation, flatulence, abdominal pain, steatorrhea)
- Gallstones
Inhibit the release of GH, insulin, glucagon, gastrin
- Parenteral administration
- Regular formulation – inject 2-4 times daily
- Slow-release formulation – inject every 4 w’
- Acromegaly (pituitary adenoma), gigantism
- Endocrine tumors (carcinoid, gastrinoma, glucagonoma,
insulinoma, VIPoma) - Control of bleeding from esophageal varices
Side effects: GI disturbances, steatorrhea (due to impaired pancreatic secretion), gall stone, cardiac conduction abnormalities
