Krabbamein og lyf gegn þeim

1. Krabbamein og lyf gegn þeim Ólafur Baldursson dr. med

2. Background: Hairy cell leukemia (HCL) is one of the chronic lymphoid leukemias originally described in 1958 by Borouncle and coworkers. HCL is a B-cell disease, and the abnormal cell has hairlike cytoplasmic projections on its surface. • Pathophysiology: The abnormal cell is a clonal B-cell lymphocyte (see Image 1). It infiltrates the patient's reticuloendothelial system and interferes with bone marrow function, resulting in failure or pancytopenia. It also infiltrates the liver and spleen, resulting in organomegaly. • The etiology of HCL has not been determined, although some investigators suggest that exposures to benzene, organophosphorous insecticides, or other solvents may be related to disease development. This hypothesis has not been confirmed by other reports. Exposure to radiation, agricultural chemicals, and wood dust, and a previous history of infectious mononucleosis, have been suggested as etiologic associations in previous reports. • Frequency: • In the US: HCL is relatively uncommon and accounts for 1-2% of all leukemia cases. • Internationally: Some geographic variations have been observed, such as an extremely low incidence in Japan. • Mortality/Morbidity: • Symptoms of pancytopenia are related to anemia (fatigue and weakness), thrombocytopenia (bleeding or easy bruising), and neutropenia (infections). • Abdominal discomfort is a common symptom, resulting from hepatosplenomegaly. It usually is controlled with new effective drug therapy, although late recurrences may occur. Recurrences usually are responsive to medications.

3. Krabbamein Ólafur Baldursson Krabbamein • Skilgreiningar • Sjálfstæð fjölgun frumna sem ryður eðlilegum frumum úr vegi og dreifir sér um líkamann með blóði eða sogæðum • Carcinogenesis, mynd 12.1

5. Krabbamein Ólafur Baldursson Krabbamein • Orsakir • Samspil erfða og umhverfis • Þáttur erfða er mismikill (tvíburarannsóknir) • Blöðruhálskirtilskrabbamein 42% • Ristilkrabbamein 35% • Brjóstakrabbamein 25%

6. Krabbamein Ólafur Baldursson Krabbamein • Orsakir frh. • Umhverfisþættir • Helicobacter pylori • Epstein Barr vírus • Human papilloma vírus • Hepatitis B eða C • Sveppir sem framl. Aflatoxín • Efni, benzene o.fl.

7. Krabbamein Ólafur Baldursson Krabbamein Orsakir - gen Oncogen • Gen sem stjórna vexti frumna • DNA raðir sem skrá prótín sem eru vaxtarþættir frumna • c-myc, c-fos, c-jun Tumor suppressor gen • P53 – Li-Fraumeni syndrome • rb – Retinoblastoma Apoptosis • programmed cell death • Pro-apoptosis prótín; Bad og caspases • Anti-apoptosis prótín; Bcl-2

8. Disease characteristics. Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with soft-tissue sarcoma, breast cancer, leukemia, osteosarcoma, melanoma, and cancer of the colon, pancreas, adrenal cortex, and brain. Individuals with LFS are at increased risk for developing multiple primary cancers. Age-specific cancer risks have been calculated. Diagnosis/testing. LFS is diagnosed in individuals meeting established clinical criteria. More than 50% of individuals diagnosed clinically have an identifiable disease-causing mutation in the TP53gene. Of these mutations, 95% can be detected by sequence analysis, which is clinically available.

9. Krabbamein Ólafur Baldursson Krabbamein Orsakir Eðlileg afritun DNA bilar DNA-viðgerðar-gen eru stökkbreytt í ristilkrabba Krabbameinsfrumur eru “ódauðlegar”

10. Krabbamein Ólafur Baldursson Krabbamein • Líffræðilegir eiginleikar • Frumufjölgun • Stjórnunarprótín bila • Óstöðugleiki í DNA • “Ódauðleiki” • innrás í aðliggjandi vefi • Útrás í æðakerfið • Örva angiogenesis

11. Krabbamein Ólafur Baldursson Krabbamein • Tvennt ræður mestu um horfur sjúklinga: • Vefjafræðileg greining • Small cell vs. non small cell lungnakrabbi • Lymphoma; Hodgkins vs. non-Hodgkins • Stigun

12. Krabbamein Ólafur Baldursson Krabbamein • Frumum fjölgar mishratt í líffærum - Hratt: Beinmergur, slímhúð meltingarfæra, kynfrumur, hárslíður • Hægt: Öndunarfæraslímhúð, lifur, nýru, innkirtlar • Engin fjölgun: Vöðvar beinagrindar, hjarta, bein, taugar • Krabbamein vaxa mishratt • Tvöföldunartímar • Hodgkins og osteosarcoma: 30-70 dagar • Lungnakrabbi og ristilkrabbi > 70 dagar

13. During development from stem to fully differentiated, cells in the body alternately divide (mitosis) and "appear" to be resting (interphase). This sequence of activities exhibited by cells is called the cell cycle. • Interphase, which appears to the eye to be a resting stage between cell divisions, is actually a period of diverse activities. Those interphase activities are indispensible in making the next mitosis possible. • Interphase generally lasts at least 12 to 24 hours in mammalian tissue. During this period, the cell is constantly synthesizing RNA, producing protein and growing in size. By studying molecular events in cells, scientists have determined that interphase can be divided into 4 steps: Gap 0 (G0), Gap 1 (G1), S (synthesis) phase, Gap 2 (G2). • Gap 0 (G0): There are times when a cell will leave the cycle and quit dividing. This may be a temporary resting period or more permanent. An example of the latter is a cell that has reached an end stage of development and will no longer divide (e.g. neuron). • Gap 1 (G1): Cells increase in size in Gap 1, produce RNA and synthesize protein. An important cell cycle control mechanism activated during this period (G1 Checkpoint) ensures that everything is ready for DNA synthesis. (Click on the Checkpoints animation, above.) • S Phase: To produce two similar daughter cells, the complete DNA instructions in the cell must be duplicated. DNA replication occurs during this S (synthesis) phase. • Gap 2 (G2): During the gap between DNA synthesis and mitosis, the cell will continue to grow and produce new proteins. At the end of this gap is another control checkpoint (G2 Checkpoint) to determine if the cell can now proceed to enter M (mitosis) and divide. • Mitosis or M Phase: Cell growth and protein production stop at this stage in the cell cycle. All of the cell's energy is focused on the complex and orderly division into two similar daughter cells. Mitosis is much shorter than interphase, lasting perhaps only one to two hours. As in both G1 and G2, there is a Checkpoint in the middle of mitosis (Metaphase Checkpoint) that ensures the cell is ready to complete cell division. Cell cycle http://www.cellsalive.com/cell_cycle.htm http://www.cellsalive.com/mitosis.htm

14. Interphase: Cells may appear inactive during this stage, but they are quite the opposite. This is the longest period of the complete cell cycle during which DNA replicates, the centrioles divide, and proteins are actively produced. Prophase: During this first mitotic stage, the nucleolus fades and chromatin (replicated DNA and associated proteins) condenses into chromosomes. Each replicated chromosome comprises two chromatids, both with the same genetic information. Microtubules of the cytoskeleton, responsible for cell shape, motility and attachment to other cells during interphase, disassemble. And the building blocks of these microtubules are used to grow the mitotic spindle from the region of the centrioles. Prometaphase: In this stage the nuclear envelope breaks down so there is no longer a recognizable nucleus. Some mitotic spindle fibers elongate from the centrioles and attach to kinetichores, protein bundles located on the chromosomes. Other spindle fibers elongate but instead of attaching to chromosomes, overlap each other at the cell center. Metaphase: Tension applied by the spindle fibers aligns all chromosomes in one plane at the center of the cell. Anaphase: Spindle fibers shorten, the kinetichores separate, and the chromatids (daughter chromosomes) are pulled apart and begin moving to the cell poles. Telophase: The daughter chromosomes arrive at the poles and the spindle fibers that have pulled them apart disappear. Cytokinesis: The spindle fibers not attached to chromosomes begin breaking down until only that portion of overlap is left. It is in this region that a contractile ring cleaves the cell into two daughter cells. Microtubules then reorganize into a new cytoskeleton for the return to interphase.

15. ONCOLOGYPrinciples of chemotherapy Electron micrographof mitoticcell

16. Krabbameinslyfjameðferð Stig mítósunar Prophase Interphase Telophase Metaphase Anaphase

17. Krabbamein Ólafur Baldursson Krabbamein • Lyfjameðferð, mörg lyf • Hvert lyf um sig verður að vera virkt gegn krabbameinsfrumum • Saman þurfa lyfin að drepa sem næst 100% krabbameinsfrumnanna • Verkunarmáti lyfjanna sé misjafn • Aukaverkanir séu ólíkar

18. Krabbamein Ólafur Baldursson Krabbamein • Síðkomnar aukaverkanir lyfjameðferðar Vanstarfsemi kynkirtla (gonadal dysfunction) • Alkylerandi lyf og geislun • 80% karla með Hodgkin´s meðh. með MOPP:Mechlorethamine, vincristine, procarbazine, prednisolone verða ófrjóir en helmingur þeirra nær sér á 4 árum • Konur: amenorrhea, vaginal atrophy, endometrial hyperplasia eru skammtaháðar aukaverkanir og algengari með vaxandi aldri

19. Krabbamein Ólafur Baldursson Krabbamein • Síðkomnar aukaverkanir lyfjameðferðar • Carcinogenesis • Alkylerandi lyf hafa tilhneigingu til að valda hvítblæði eða eitlakrabba 3-7 árum eftir að meðferð hefst • Valda stökkbreytingum – bein áhrif á DNA • Lyfjameðferð eggjastokkakrabbameins eykur líkur á hvítblæði 27 falt • Melphalan meðferð á brjóstakrabba eykur líkur á hvítblæði 7 falt • Myeloma meðhöndlað með melphalan; 214 falt líklegra að fá hvítblæði • Brjóstakrabba-meðferð með cyclophosphamíð, MTX og 5-FU: Ekki auknar líkur á hvítblæði eftir 20 ár

20. Krabbamein Ólafur Baldursson Krabbamein • Síðkomnar aukaverkanir lyfjameðferðar • Carcinogenesis • Myelodysplasia • Ýmis krabbamein

21. Krabbamein Ólafur Baldursson Krabbamein • Viðnám gegn krabbameinslyfjameðferð • Genetic resistance • MDR genið framleiðir MRP • Pumpar lyfjum út úr frumum • “Felustaðir”, “pharmacologic sanctuaries” • Heili • Eistu • Sýrustig utan frumna lágt í mörgum æxlum, jóníserar sum lyf t.d. doxorubicin

22. Flokkun krabbameinslyfja Mítósu- hemlar And-efnaskipta lyf Alkylerandi lyf Tópóísómer- Asahemlar (sýklalyf) Önnur Cyclópfospfamíd Methótrexat Vinkristín Doxorubicin L-asparaginase Ífosfamíd 5- Flúróúrasil Vinblastín Epirubicin Hydroxyurea Cisplatin Arabinósid Vinorelbín Daunorubicin Procarbazine Melphalan Mercaptopurin Taxanar Bleomycin Kllórambúcil Etoposid Mitomycin-c Karmustin Mitoxantron Estramústin Camptothecin

24. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem verka beint á DNA • Alkylerandi lyf • Paul Ehrlich • Methyl nitrosourea 1898 • Sulfur mustard gas í fyrri heimstyrjöld • Nitrogen mustard (mechlorethamine)1943 US Army • Efnaslys ollu fækkun lymphocyta • Gefið sjúklingum með “malignant lymphoproliferative” sjúkdóma

25. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem verka beint á DNA • Alkylerandi lyf • Covalent binding alkyl hóps við DNA • Mjög stuttur helmingunartími, 10 mín-1.8 klst. • Chlorambucil frásogast vel (50%), T1/2=1.5-3 klst • Óháðir nýrna- og lifrarbilun að mestu

27. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem verka beint á DNA • Alkylerandi lyf (öll forlyf) • Mechlorethamine • Melphalan • Chlorambucil • Ifosphamide (lengstur T1/2) • Cyclophosphamide • Procarbazine og dacarbazine

28. Krabbamein Ólafur Baldursson Krabbameinslyf • Alkylerandi lyf – Aukaverkanir • Myelosuppression (verri ef meðferð áður) • Ógleði, uppköst • Teratogenesis • Leukemogenesis • Carcinogenesis • Alopecia (cyclophosphamide) • Interstitial pneumonitis (nitrosourea, busulfan) • Nýrnabilun (cyclo- og ifos) • Hemorrhagískur cystitis (cyclo- og ifos)

29. CYCLOPHOSPHAMIDE HEPATIC CYTOCHROMES P 450 ACTIVATION INACTIVATION 4-KETOCYCLOPHOSPHAMIDE CARBOXYPHOSPHAMIDE 4-OH CYCLOPHOSPHAMIDE ALDOPHOSPHAMIDE ALDEHYDE DEHYDROGENASE PHOSPHORAMIDE MUSTARD ACROLEIN CYTOTOXICITY TOXICITY

30. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem verka beint á DNA frh. • Nitrosourea • Carmustine, lipophil – kjörlyf á æxli í miðtaugakerfi • Bólga og örmyndun í lungum (isocyanate niðurbrotsefni)

31. Krabbamein Ólafur Baldursson Krabbamein • Lyf sem verka beint á DNA frh. • Platinum • 1968 fundust áhrif þessara efna á bakteríur • Cisplatin • Binst guanine í DNA og RNA • Afvindur og styttir DNA • inactiverast við prótein-bindingu en ekki við niðurbrot • 90% útskilst með þvagi • Aukaverkanir • Nýrnabilun algeng • Myelosuppression sjaldnar • Neuropatia • Heyrnarleysi, ofnæmi, ógleði og uppköst algengar aukaverkanir • Analog • Carboplatin

32. Krabbamein Ólafur Baldursson Krabbamein • Lyf sem verka beint á DNA frh. • Cisplatin • Gjörbreytti meðferð krabbameins í eistum • Nú læknast 70-90%, jafnvel með meinvörp • Áður 5-15 %

33. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem skemma DNA óbeint • Anthracycline • Doxorubicin, daunorubicin, idarubicin • Mitoxantrone • Lyf gegn topoisomerasa • Etoposide • Camptothecin • Ýmis • Bleomycin • Dactinomycin • Mitomycin C

34. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem skemma DNA óbeint • Anthracycline • Doxorubicin notað gegn • Lymphoma (Hodgkin´s og NHL) • Hvítblæði • Krabbameini í brjóstum, lungum, maga og skjaldkirtli • Sarcoma • Daunorubicin helst notað gegn hvítblæði (minni serositis en af doxo)

35. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem skemma DNA óbeint • Anthracycline • Doxorubicin • Virka lyfið er idarubicin • Binst topoisomerasa II • Og mynda fría radicala • Cardiotoxískt (samanlagður skammtur) • Losun á Calcium intracellulert • Ca tekið inn í mitochondria • Aktín og mýósín skemmast • Hjartavöðvinn rýrnar • Skortur á catalasa í hjarta en hann vinnur gegn fríum radikölum • Epirubicin, minni áhrif á hjartað

36. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem skemma DNA óbeint • Anthracycline • Doxorubicin • Flyst passívt inn í frumur, ójóníserað • Lágt sýrustig í og við æxli, jóníserar lyfið og hindrar upptöku þess • T1/2 er um 30 klst • Betra að gefa vikulega í hægri infusion þar sem áhrif á hjarta eru háð hámarksstyrk í blóði • Aðeins idarubicin til í oral-formi. Notað í hvítblæði og brjóstakrabba

37. Krabbamein Ólafur Baldursson Krabbameinslyf • Anthracycline • Aukaverkanir • Myelosuppression • Mucositis • Stomatitis • Mikið drep í húð ef út fyrir æðalegg • Hjartabilun • Áhættuþættir • Háþrýstingur • Fyrri saga um hjartasjúkdóma

38. Krabbamein Ólafur Baldursson Krabbameinslyf • Lyf sem skemma DNA óbeint • Bleomycin • Glycopeptíð einangruð úr Streptomyces • Járnbindandi, Fe+2 • Fe+2-bleomycin-súrefnis complex binst DNA sem klofnar • Brotið niður af bleomycin hydrolasa • Minna er af honum í húð og lungum • Notað gegn: Lymphoma, krabbameini í eistum, leghálsi, höfði • Eituráhrif á lungu eru veruleg • Interstitial pneumonitis - fibrosis

39. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • Methotrexate • Pyrimidine analogar • 5-fluorouracil • Cytarabine • Gemcitabine • Hydroxyurea • Purine antimetabolitar • Azathioprine • Fludarabine

40. Purines • Adenine = 6-amino purine • Guanine = 2-amino-6-oxy purine • Pyrimidines • Uracil = 2,4-dioxy pyrimidine • Thymine = 2,4-dioxy-5-methyl pyrimidine

41. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • Methotrexate • Blokkar dihydrofolate reductase • Minnkuð framleiðsla á thymidine • Frásog frá meltingarvegi gott en breytilegt • Útskilið um nýru

43. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • Methotrexate-aukaverkanir • Myelosuppression • Mucositis • interstitial pneumonitis

44. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • Pyrimidine-analogar • 5-fluorouracil • Charles Heidelberger 1957, aukin uracil upptaka í lifraræxli í rottum • Forlyf, ribosylerað og phosphorylerað • 5-fluoro-deoxyuracil monophosphate • Blokkar thymidilate synthase • Einnig einhver bein áhrif á DNA og RNA • Frásog frá meltingarvegi slæmt

45. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • 5-fluorouracil • Blokkar thymidylate synthase • Mikið notað með öðrum krabbameinslyfjum • Leucovorin (folinic sýra), reduceruð fólín sýra, blokkar thymidylate synthasa og eykur þannig áhrif 5-FU • Leucovorin tvöfaldar árangur 5-FU meðferðar við ristilkrabba og brjóstakrabba

46. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • 5-fluorouracil – Aukaverkanir • Myelosuppression • Mucositis • Niðurgangur • Palmar erythema (ef löng meðferð) • Cerbellar ataxia (sjaldan)

47. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • Aðrir pyrimidine-analogar • Cytarabine (Ara-C) • Gemcitabine • Hydroxyurea • 100 ára gamalt • Blokkar ribonucleotide reductasa • Aðallega gegn CML • Leucopenia algeng • Almennt stuttvirkt og viðsnúanleg áhrif

48. Krabbamein Ólafur Baldursson Krabbameinslyf • Antimetabolitar • Purine antimetabolitar • 6-mercaptopurine og 6-thioguanine • Hitching og Elion • Rannsóknir á þvagsýrugigt 1940-50 • Nóbelsverðlaun 1988 • Azathioprine er forlyf 6-MP • Mikið notað í ónæmisbælingu • Allopurinol getur leitt til eitrunar • Fludarabine

50. Krabbamein Ólafur Baldursson Krabbameinslyf • Tubulin-binding agents • Vinca alcaloidar • Vincristine • Vinblastine • Paclitaxel