Molecular tumor biology 7.Molecular basics of anti-tumor
therapies 2.Dr. Gábor Mátis
University of Veterinary MedicineDivision of Biochemistry
26 April 2018
Topics of the lecture
The molecular basics of anti-tumor therapies 2.• Irradiation (radiotherapy)• Endocrine therapy• Targeted therapies• Biological therapies – immune therapy• Novel, special therapeutical approaches:
– Photodynamic therapy– Local chemotherapy– Electrochemotherapy– Ultrasound sensitization– Thermotherapy – oncotermia
• Supplemental therapies
Molecular basics of radiotherapy
• Local/regional therapy with ionizing radiation• Types of radiation:
– β radiation = high electrons– ɤ radiation = high energy EM radiation (photons)– α radiation = He nuclei– Neutron radiation
• Quantitative measures: dose Gray (Gy) =J/kg
Comparison of radiation types
Mechanisms of radiotherapy
• Indirect: irradiation energy transmissionionization production of free radicals (ROS)damage of macromolecules (DNA, proteins)
• Direct: irradiation energy transmissiondamage of macromolecules (DNA, proteins) dueto ionization
• Damaged macromolecules inflammation,repair mechanisms apoptosis, loss ofproliferative potential or survival
• Intensively proliferating cells are more sensitiveto oxidative stress selective effects
Mechanisms of radiotherapy
mdpi.com;courses.ecampus.oregonstate.edu
Immune-mediated systemic effects ofradiotherapy
Practical aspects of radiotherapy• Daily therapy is required (fractionated
radiotherapy)• Precise positioning and dosing are important• Veterinary practice: in narcosis• Neoadjuvant, adjuvant or palliative goal
kutyadaganat.com
Side effects of radiotherapy• Local inflammation – skin leasions• Necrotic, fibrotic processes• Periorbital tumors: cornea destruction
todaysveterinarypractice.navc.com
Mechanisms of tumor repopulation afterradiotherapy 1.
Tumor-associated macrophages: NO production nitrosylation of HIF-1αinhibition of VHL binding hypoxia-independent HIF-1α activation
Mechanisms of tumor repopulation afterradiotherapy 2.
Intrinsic pathway of apoptosis activation of caspase 3 activation ofphospholipase A2 arachidonic acid COX-2 PGE2 production
Brachytherapy
Medical Tourism Consultants India; Nick Brook Urology
Endocrine anti-tumor therapy
• Antiestrogens:– Tamoxifen, raloxifen: SERM = selective estrogen receptor modulators
(both agonist and antagonist effects) competing with 17β-estradiol– Fulvestrant: only antagonistic effect
• Gestagens:– Medroxiprogesteron, megestrol: inhibition of FSH, LH, ACTH
production hormone synthesis in ovaries is stopped• Antiprogestinesk: blocking progesteron receptors• Aromatase inhibitors: inhibiting the androstendion estron
reaction (post-menopausal state) – e.g. anastrosol (non-steroid)• GnRH-analogues: agonists (buserelin, goserelin) and antagonists• Androgen blocade: treating prostate cancer
• Molecular diagnostics:– Monitoring (proto-)oncogens and tumor
suppressor genes– Mutations and alterations of gene expression
• More signalling pathways can be involved• Investigating the points of alterations
molecular targets of the therapy
Targeted anti-tumor therapy
Targeted anti-tumor therapy
Targeted therapy: monoclonal antibodies + lowmolecular mass inhibitors
(HER-2 positive mammary tumors)
Trastuzumab HER-2 inhibitionLapatinib tyrosine kinase inhibition
Targeted therapy: monoclonal antibodies + lowmolecular mass inhibitors
– inhibition of VEGF signalling
Bevacizumab VEGFinhibitionSorafenib tyrosinekinase inhibition
alcethron.com; indiamart.com
Targeted therapies – molecular targets
Indian Journal of Pharmacology
Oncogenic pathways and targetedtherapeutical possibilities for
adenocarcinomas
Biological therapy – immune therapy
nanalyze.com
Biological therapy – immune therapy
Photodynamic therapy
sciencedirect.com
Local/regional chemotherapy
• Local vs. systemic (traditional)chemotherapy
• Benefits:– Better efficiency– Reduced side-effects
• Application forms:– Injection into the tumor– Implants
• Biomaterial-based drug-delivery:gelatin, PEG, polyuretane,cellulose, hydrogels…
researchgate.net
Electrochemotherapy
en.wikipedia.org
Electrochemotherapy
cancerres.aacrjournals.org
Sensitization with ultrasound
dev.fusfoundation.org
Thermotherapy – oncothermia
pubs.rsc.org
Supplemental therapies• Antioxidants
– In high dose: prooxidants!– Contraindicated:
• Radiotherapy• Certain types of chemotherapy: e.g.
cisplatin
• Plant extracts, fungi, feedsupplements…– Usually no clear scientific
evidence for efficiency– No magical treatments!
Successful combination of anti-tumortherapeutical modalities
researchgate.net