Molecularbasicsofanti-tumor

Question 1

Molecular basics of radiotherapy

Answer 1

• 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

Question 2

Mechanisms of radiotherapy

Answer 2

• Indirect :irradiation=>energy transmission=> ionization=>free radicals(ROS)=> DNA + protein damage
• Direct: irradiation=>energy transmission damages DNA, proteins due to ionization

• Intensively proliferating cells are sensitive to oxidative stress

Question 3

Practical aspects of radiotherapy

Answer 3

• Daily therapy is required(fractionated radiotherapy)
• Precise positioning and dosing are important
• Veterinary practice: in narcosis
• Neoadjuvant, adjuvant or palliativegoal

SEs:
• Local inflammation–skin lesions
• Necrotic, fibrotic processes
• Periorbital tumors :cornea destruction

Question 4

Mechanisms of tumor repopulation after radiotherapy

Answer 4

1. Tumor-associated macrophages: NO production=>nitrosylation of HIF-1α=>inhibition of VHL binding=>hypoxia-independent HIF-1α activation
2. Intrinsic pathway of apoptosis=>activation of caspase3=> activation of phospholipaseA2 =>arachidonic acid=>COX-2=>PGE2 production

Question 5

Endocrine anti-tumor therapy

Answer 5

• Antiestrogens:
– Tamoxifen, raloxifene: SERM=
selective estrogen receptor modulators (both agonist + antagonist effects)=> competing w/ 17β-estradiol
– Fulvestrant: only antagonistic effect
• Gestagens:
– Medroxyprogesterone, megestrol: inhibition of FSH, LH, ACTH production=> hormone synthesis in ovaries stopped
• Antiprogestinesk: blocks progesterone receptors
• Aromatase inhibitors: inhibits androstendion=> estrone reaction(post-menopausal state)–e.g. anastrozole (non-steroid)
• GnRH-analogues: agonists (buserelin, goserelin) & antagonists
• Androgen blockade: treating prostate cancer

Question 6

Targeted anti-tumor therapy

Answer 6

• Molecular diagnostics:
–Monitoring(proto-)oncogenes & tumor suppressor genes
–Mutations & alterations of gene expression
• Multiple signalling pathways may be involved
• Investigating the points of alterations=> molecular targets of the therapy

monoclonal Abs + low molecular mass inhibitors (HER-2 positive mammary tumors)
Trastuzumab=> HER-2 inhibition
Lapatinib => tyrosine kinase inhibition

monoclonal Abs + low molecular mass inhibitors –inhibition of VEGF signalling
Bevacizumab => VEGF inhibition
Sorafenib=>tyrosine kinase inhibition

Question 7

Local/regional chemotherapy

Answer 7

• Local vs. systemic(traditional) chemotherapy 
• Benefits: 
– Better efficiency 
– Reduced SEs
• Application forms: 
– Injection into the tumor 
– Implants 
• Biomaterial-based drug-delivery: gelatin, PEG, polyurethane, cellulose, hydrogels…

Question 8

Others

Answer 8

Brachytherapy
Photodynamic therapy
Electrochemotherapy
Sensitization with ultrasound
Thermotherapy–oncothermia

Question 9

Supplemental therapies

Answer 9

• Antioxidants
–In high dose: prooxidants!
–Contraindicated for Radiotherapy & Certain types of chemotherapy: e.g. cisplatin
• Plant extracts, fungi, feed supplements… –Usually no clear scientific evidence for efficiency