Inleiding in de tumorbiologie (4)

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1 Inleiding in de tumorbiologie (4)
Keuzemodule TBK01 Inleiding in de tumorbiologie (4)

2 Behandelingsmethoden / therapieën
Doel: lichaam vrijmaken van kankercellen of aantal terugbrengen De drie conventionele therapieën: Chirurgie Radiotherapie (bestraling) Chemotherapie

3 Chirurgie Solide, goed gelokaliseerde tumoren
Omliggend weefsel onderzocht op invasie Lymfeknopen (zegt iets over kans op uitzaaiing) Risico afhankelijk van grootte en locatie Grillig? Onontdekte uitzaaiingen

4 Radiotherapie Bestraling (X-ray) leidt tot vorming van zuurstofradikalen Zuurstofradikalen leiden tot DNA-schade DNA-schade leidt tot apoptose Nadelen: Ook gezonde cellen gedood, leidend tot bijvoorbeeld misselijkheid, diarree, infecties, bloedarmoede, haaruitval.

5 Ioniserende straling Rammen steriliseren Doodt delende cellen
Meestal bestraling van buitenaf, soms implantaat Beperkt bereik Delende cellen (G2 en mitose zijn gevoelig) (G1 en S fase meer DNA reparatie mechanismen) Herhaling om schadeherstel te beperken.

6 Ioniserende straling Ioniserend → radicaalvorming
Zuurstof moleculen worden omgezet in radicalen als H2O2, OH en O2- DNA schade en hopelijk apoptose Lage zuurstofspanning, minder gevoelig (slecht doorbloede tumoren) Ook sterfte gezonde delende weefsels misselijkheid, diarree, infecties, bloedarmoede Soms schade aan niet delende weefsels (bij hoge doseringen) Alternatief: implantatie van radioactieve metaaldraadjes (Iridium-192)

7 Cytotoxische chemotherapie
Werkt ook op delende cellen (1e wereldoorlog, mosterdgas. Naast acute dodelijke effecten ook chronische: bloedarmode en atrofie lymfeklieren. Behandeling lymfeklierkanker.) Vergelijkbare bijwerkingen als bestraling, maar dan systemisch! (haaruitval, misselijkheid, bloedarmoede)

8 Cytotoxische chemotherapie
Doseringsprobleem: Smalle marge tussen minimaal effectieve dosis en maximaal tolereerbare dosis Dosisbeperkende weefsel (MTD= maximaal tolereerbare dosis)

9 chemotherapie Oraal Injectie (infuus)
Stof komt overal, dit is zowel een nadeel als een voordeel Minder effectief bij slecht doorbloede metastasen Meeste stoffen belemmeren celdeling (cytostatica)

10 Anatomy of an Antibody-Drug Conjugate (ADC)
Linker stable in circulation Antibody targeted to tumor Linker biochemistry Acid labile (hydrazone) Enzyme dipeptides (cleavable) Thioether (uncleavable) Hindered disulfide (uncleavable) Site of conjugation Fc, HC, LC Humanized monoclonal Ab (IgG1) mAb with Fc modifications (modulate ADCC, CDC activity) Other mAb fragments Very potent chemotherapeutic drug Antibody drug conjugates are a unique type of therapeutic agent that is a hybrid of a large molecule and small molecule. ADCs consist of an antibody targeted to a tumor antigen attached to a highly potent cytotoxic drug by means of relatively stable linker. Antbody: The type of antibody used in ADCs are usually IgG1. This particular class of antibody can trigger antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC). In the context of an Adc, modulation of the Fc portion of the mAb may be desirable to alter the ability of the antibody to trigger ADCC or CDC immune responses, since this type of activity may not be desirable to the efficacy or safety of conjugate. In addition, modulation of the Fc portion may be desirable to inhibit triggering of a specific signaling cascade. An alternative to using a full length or Fc modulated Ab in ADCs, is to use a fragments of the mAb (such as Fabs). Cytotoxin: A number of different classes of cytotoxins are available for the treatment of cancer. These drugs target rapidly proliferating cells by disrupting different aspects of cellular proliferation, inluding DNA replication, repair, translation, and cell division. Because cancer cells have a higher rate of cell proliferation than normal cells, cancer cells are more susceptible to cytotoxic effects of these drugs; however it should be noted that the cytotoxins are not specific for cancer cells. The cytotoxins commonly used in ADCs fall into two categories: those that target microtubules (tubulin polymerization inhibitors) and DNA damaging agents. The maytansines (DM1) and the auristatins(MMAE) are compounds that inhibit microtubule assembly. The maytansines and their derivatives were discovered in the early 1970s and were shown to be 100 to 1000-fold more potent than other microtubule inhibitors such as vinblastine. Similarly, auristatins (MMAE) which are synthetic analogs of dolastatin, have been shown to be 50 to 200-fold more potent than doxorubicin. Aside from high potency, other desirable characteristics of a cytotoxin suitable for ADCs are good solubility and stability in aqueous soltions, low MW, accessibility of reactive groups for conjugation and low immunogenicity. Linker: the linker is a critical part of the multicomponent ADC. There are generally two classes of linkers based on their biochemistry; cleavable and uncleavable. Acid labile linkers undergo hydrolysis in the acidic environment (associated with non-specific release of the drug in clinical studies); peptide-based linkers which utilize a peptide bond to link the Ab to drug and undergo hydrolysis by intracellular lysosomal proteases. Hindered disulfide linkers are selectively cleaved in the cytosol due to high intracellular concentrations of glutathione The class of thioether linkers if noncleavable and drug is likely released by intracellular proteolytic degradation. So, what’s the benefit for using such as complex multicomponent therapeutic compound to treat cancer? Tubulin polymerization inhibitors Maytansines (DM1, DM4) Auristatins (MMAE, MMAF) DNA damaging agents Calicheamicins Duocarmycins Anthracyclines (doxorubicin) Nonclinical safety evaluation of immunoconjuates Melissa M Schutten, D Antibody-Drug Conjugates: Modes of Toxicity Melissa M. Schutten, DVM, PhD, DACVP. ( 10

11 Improving the Therapeutic Window: Antibody-Drug Conjugate (ADC)
ADCs can selectively deliver a potent cytotoxic drug to tumor cells via tumor-specific and/or over-expressed antigens Increase drug delivery to tumor Reduce normal tissue drug exposure Chemotherapy ADC TOXIC DOSE (MTD) Therapeutic Window Combining a cytotoxic drug with a mAbs can provide the best of both worlds in terms of efficacy and safety. One is able to selectively deliver a highly potent cytotoxic drug to a tumor cell using the exquisitive specificity of a monoclonal ab for a particular Ag- an Ag that is either overexpressed or, preferentially, only expressed, in tumor cells. When compared to a standard chemotherapy, selectively delivering a potent cytotoxin to a tumor using an ADC allow you to deliver a much higher dose of drug to your cell of interest while effectively increasing the window b/w your toxic dose and minimally efficacious dose. So, let’s look at an example of the advantages that ADCs have over standard “chemo”: TOXIC DOSE (MTD) DRUG DOSE Therapeutic Window EFFICACIOUS DOSE (MED) EFFICACIOUS DOSE (MED) MTD: Maximum tolerated dose; MED: Minimum Efficacious Dose Nonclinical safety evaluation of immunoconjuates Melissa M Schutten, D Antibody-Drug Conjugates: Modes of Toxicity Melissa M. Schutten, DVM, PhD, DACVP. (

12 Cytostatica blokkeren voortgang van de celcyclus
Aangrijpingspunten G1 (zelden) S (vaak) G2 (zelden) M (vaak)

13 Camptothecine een topoisomerase remmer
Maar ook: Irinotecan, Topotecan

14 Fig Primase Single-strand binding proteins 3 5 3 RNA primer Topoisomerase 5 5 3 Helicase

15 Fluorouracil een DNA synthese remmer
thymine deoxyribose

16 (a) Polynucleotide, or nucleic acid (c) Nucleoside components: sugars
Fig. 5-27 5 end Nitrogenous bases Pyrimidines 5C 3C Nucleoside Nitrogenous base Cytosine (C) Thymine (T, in DNA) Uracil (U, in RNA) Purines Phosphate group Sugar (pentose) 5C Adenine (A) Guanine (G) 3C (b) Nucleotide Fluorouracil Sugars 3 end (a) Polynucleotide, or nucleic acid Deoxyribose (in DNA) Ribose (in RNA) (c) Nucleoside components: sugars

17 Vinca alkaloïden vincristine en vinblastine (mitose remmers)
Afbraak microtubili tubuline vimentine

18

19 Mitose - Cytokinese Tubuline Tubuline

20 Taxol duur, eierstokkanker. Voorkomt afbraak micotubili.

21 Niet celcyclus specifieke cytostatica
DNA binnendringing. Verhindering replicatie. Diverse alkylerende stoffen die gemakkelijk allerlei dwarsverbindingen binnen grote moleculen kunnen maken zoals eiwitten en DNA. Ze verhinderen dan de DNA replicatie, bv. Cyclophosphamide, een afgeleide van mosterdgas.

22 Multidrug resistentie
MDR-1 een membraangebonden pompeiwit.

23 “Biotherapie” Er zijn veel (experimentele) therapieën waarbij gebruik gemaakt wordt van biologische signaalstoffen of antagonisten daartegen b.v. Hormonen, groeifactoren, antilichamen etc……

24 Gleevec bij Chronische Myeloïde Leukemie (CML)
Bcr-Abl fusie eiwit (tyrosine-kinase activiteit)

25 Tamoxifen bij borstkanker
Tamoxifen blokkeert de binding van oestrogenen aan hun receptor (oestrogeen-antagonist) estradiol

26 Resistentie tegen anti-oestrogeentherapie

27 Nieuwe therapieen, bijv. VEGF targeting: