New England Journal of Wind 2011 Jan;1(3): 6-10
Target Therapy & Monoclonal Antibodies
Wei-Lun Chang
Tyrosine Kinase Inhibitors (TKIs)
Imatinib (Gleevec® 基利克) [eye MAT eh nib]
Pharmacologic Category: TKI
Mechanisms: Multi-TKI
* Inhibit the Bcr-Abl, PDGFR, SCR, c-Kit
[Gleevecs mechanism of Action]
Dasatinib (Sprycel® 柏萊) [da SA ti nib]
Pharmacologic Category: TKI
Mechanisms: Multi-TKI
* Inhibit the Bcr-Abl (tightly binding), SRC family (SRC,
LKC, YES, FYN); c-Kit, EPHA2 & PDGFR-beta
Nilotinib (Tasigna® 泰息安) [nye LOE ti nib]
Pharmacologic Category: TKI
Mechanisms: Multi-TKI
* Inhibit the Bcr-Abl, PDGFR, c-Kit
Tyrosine Kinase Inhibitors (TKIs) & VEGF Inhibitors
[VEGF pathway: Target several targeted therapies against cancer Avastin Sutent Nexavar]
Sorafenib (Nexavar® 蕾沙瓦) [sor AF e nib]
Pharmacologic Category: TKI
Mechanisms: Multi-TKI / VEGF Inhibitor
* Inh. Intracellular RAF kinases (CRAF, BRAF), MEK, ERK
* Inh. Cell surface Kinase receptors (c-Kit, VEGFR-2, VEGFR-3,
PDGFR-beta, & FLT-3)
[Cancer: Sorafenib (Nexavar) English]
Sunitinib (Sutent® 紓癌特) [su NIT e nib]
Pharmacologic Category: TKI
Mechanisms: Multi-TKI / VEGF Inhibitor
* Inh. Multi-TK & VEGFR-1, 2 & 3, FLT-3, PDGFR-alpha & beta, CSF-1R
* Similar to Sorafenib
EGFR & Tyrosine Kinase Inhibitors (TKIs)
Lapatinib (Tykerb® 泰嘉錠) [la PA ti nib]
Pharmacologic Category: TKI
Mechanisms: Dual Kinases Inhibitor
* Inh. EGFR (ErbB1) & HER2 (ErbB2) by binding to intracellular kinase domains,
blocking Erk1/2 & Akt.
[Mecanismo Tykerb]
Gefitinib (Irresa® 艾瑞莎) [ge FI tye nib]
Pharmacologic Category: EGFR-TKI
Mechanisms:
* Block the signal transduction pathways of EGFR-TK.
Erlotinib (Tarceva® 得舒緩) [er LOE tye nib]
Pharmacologic Category: EGFR-TKI
Mechanisms:
* Inh. overall HER1/EGFR - TK.
* Bingding in cytosolic domain, block downstream signaling.
[Cancer: Tarceva (Erlotinib)]
Monoclonal Antibodies (MoABs)
Cetuximab (Erbitux® 爾必得舒) [se TUK see mab]
Pharmacologic Category: MoAB, EGFR Inhibitor
Mechanisms:
* Bind to EGFR & inhibit ligand-induced TK activation. (KRAS wild type)
* Cell with KRAS mutation (codon 12 or 13) may resistant to Cetuximab.
[Cancer: Cetuximab (Erbitux) English ]
Panitumumab (Vectibix® 維克替比) [pan i TOOM yoo mab]
Pharmacologic Category: MoAB, EGFR Inhibitor
Mechanisms:
* Bind to EGFR & inhibit ligand-induced TK activation. (KRAS wild type)
* Cell with KRAS mutation (codon 12 or 13) may resistant to Panitumumab.
* Semilar to Cetuximab
Trastuzumab (Herceptin® 賀癌平) [tras TU zoo mab]
Pharmacologic Category: MoAB, HER-2/neu Inhibitor
Mechanisms:
* Bind to extracellular domain of HER-2/neu
* Mediate antibody-dependent toxicity.
[Herceptin: A Multimodal Approach Targeting HER2 Positive Breast Cancer]
Gemtuzumab ozogamicin (Mylotarg® 滅髓瘤) [gem TOO zoo mab oh zog a MY sin]
Pharmacologic Category: MoAB (CD33)
Mechanisms:
* Bind to CD33 in the leukemic blasts cells and break ozogamicin linkage,
then release Calicheamicin to bind the DNA minor groove.
* Breaks double-strand DNA and cause cell death.
Alert: Withdrawal in 2010-June announced by FDA.
[Mylotarg Withdrawn from U.S. Market (Sept. 2010)]
Alemtuzumab (Campath-1H®) [ay lem TU zoo mab]
Pharmacologic Category: MoAB (CD53)
Mechanisms:
* Bind to CD52+ cells, leading antibody-dependent lysis of leukemic cells
Rituximab (Mabthera® 莫須瘤) [ri TUK si mab]
Pharmacologic Category: MoAB (CD20)
Mechanisms:
* The Fab domian would bind to the CD20 antigen on the surface of B lymphocytes.
* The Fc domain would mediate antibody- & complement-dependent B-cell lysis.
[Mechanism of Action Animation for Rituxan, a drug manufactured & marketed by Genentech]
[Copia de rituximab mec.accion]
[Acumentis Rituximab CME]
Ibritumomab (Zevalin® 澤娃靈) [ib ri TYOO mo mab]
Pharmacologic Category: MoAB (CD20), Radiopharmaceutical agent
Mechanisms:
* Is a MoAB directed against the CD20 antigen found on B lymphocytes..
* It's combined with the chelator tiuxetan, which acts as a specific chelation site
for either Indium-111 (In-111) or Yttrium-90.
* In-111 is a gamma-emitter used to assess biodistribution of Ibritumomab.
* Y-90 emits beta particles.
* Beta-emission induces celluar damage through the formation of free radicals.
(in both target cells & surrounding cells).
[Zevalin]
Tositumomab (Bexxar®) [toe si TYOO mo mab]
Pharmacologic Category: MoAB (CD20), Radiopharmaceutical agent
Mechanisms:
* Is a MoAB directed against the CD20 antigen found on B lymphocytes.
* Combined with the radioisotope Iodine (I-131) which has therapeutic &
safety implications.
* I-131 isotope can be used for imaging & dosimetry.
* The mechanisms of cell death are similar to Ibritumomab.
Bevacizumab (Avastin® 癌思停) [be vuh SIZ uh mab]
Pharmacologic Category: MoAB, VEGF inhibitor
Mechanisms:
* Preventing the VEGF association with endothelial receptors, Flt-1 and KDR.
* VEGF binding initiates angiogenesis (endothelial proliferation & the formation
of new blood vessels).
* The inhibition of microvascular growth is believed to retard the growth of all tissues.
[Cancer: Bevacizumab (Avastin) English]
Target Therapy－Proteasome Inhibitors
Bortezomib (Velcade® 萬科) [bore TEZ oh mib]
Pharmacologic Category: Proteasome inhibitor
Mechanisms:
* Inhibits proteasomes, enzyme complexes which regulate protein homeostasis
withing the cell.
* Reversibly inhibits chymotrypsin-like activity at the 26S proteasome, leading to
activation of signaling cascades, cell-cylce arrest, and apoptosis.
Target Therapy－mTOR Kinase Inhibitors
Temsirolimus (Torisel® 特癌適) [tem sir OH li mus]
Pharmacologic Category: mTOR kinase inhibitor
Mechanisms:
* Temsirolimus and its active metabolite, sirolimus, are targeted inhibitors of mTOR
(mammalian target of rapamycin) kinase activity.
* Bind to FK binding protein-12 (FKBP-12), an intracellular protein, to form a
complex which inhibits mTOR signaling, halting the cell cycle at the G1 phase
in tumor cells.
* In renal cell carcinoma, mTOR inhibition also exhibits antiangiogenesis activity by
reducing levels of HIF-1 & HIF-2 alpha (hypoxia inducible factors) and VEGF.
[mTOR抑制劑Temsirolimus Torisel 腎細胞癌的新希望-1]
[mTOR抑制劑Temsirolimus Torisel 腎細胞癌的新希望-2]
Adapted from 陳駿逸醫師 - 話聊俱樂部 http://cancerfree.medicalmap.tw/
Everolimus (Afinitor® 癌伏妥) [e ver OH li mus]
Pharmacologic Category: mTOR kinase inhibitor
Mechanisms:
* Has antiproliferative & antiangiogenic properties.
* Reduces protein synthesis & cell proliferation by binding to the FKBP-12, an
intracellular protein, to form a complex that inhibits activation of mTOR
serine-threonine kinase activity.
* It also reduces angiogenesis by inhibiting VEGF & HIF-1 expression.
Target Therapy－Immunomodulators
Thalidomide (Thado® 賽得) [tha LI doe mide]
Pharmacologic Category: Angiogenesis inhibitor; Immunomodulator;
TNF Blocking agents
Mechanisms:
* Immunomodulatory & antiangiogenic charateristics.
* May suppress excessive TNF-alpha production in patients with ENL
(erythema nodosum leprosum), yet may increase plasma TNF-alpha levels in
HIV-positive patients.
* In multiple myeloma, thalidomide is associated with an increase in natural killer
cells & increased levels of Interleukin-2 (IL-2) and Interferon-gamma.
* Other proposed mechanisms of action include suppression of angiogenesis,
prevention of free-radical-mediated DNA damage, increased cell mediated
cytotoxic effects, and altered expression of cellular adhesion molecules.
Lenalidomide (Revlimid®) [le na LID oh mide]
Pharmacologic Category: Angiogenesis inhibitor; Immunomodulator
Mechanisms:
* Immunomodulatory, Antiangiogenic & Antineoplastic charateristics.
* Selectively inhibits secretion of proinflammatory cytokines (potent inhibitor of
TNF-alpha secretion); enhances cell-mediated immunity by stmulating
proliferation of anti-CD3 stimulated T cells (resulting in increased IL-2 &
Interferon-gamma secretion).
* Inhibits trophic signals to angiogenic factors in cells.
* Inhibits the growth of myeloma cells by inducing cell cycle arrest & cell death.
=============================================
Bonus:
Treatment of Metastatic Kidney Cancer - Dr. Mary MacKenzie - Apr 10, 2010
Monoclonal Antibodies: Stanford Academia-Industry Collaboration
Direacted by Wei-Lun Chang
Pharmawind
Jan. 24th 2011
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