Krabbamein og lyf gegn þeim

Krabbamein og lyf gegn þeim

Ólafur Baldursson dr. med

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.

http://www.emedicine.com/cgi-bin/foxweb.exe/makezoom@/em/makezoom?picture=%5Cwebsites%5Cemedicine%5Cmed%5Cimages%5CLarge%5C937hcl_1000_trap.jpg&template=izoom2

Krabbamein

• Skilgreiningar– Sjálfstæð fjölgun frumna sem ryður

eðlilegum frumum úr vegi og dreifir sér um líkamann með blóði eða sogæðum

– Carcinogenesis, mynd 12.1

Krabbamein Ólafur Baldursson

Krabbamein

• Orsakir– Samspil erfða og umhverfis– Þáttur erfða er mismikill

(tvíburarannsóknir)• Blöðruhálskirtilskrabbamein 42%• Ristilkrabbamein 35%• Brjóstakrabbamein 25%


Krabbamein• Orsakir frh.

– Umhverfisþættir• Helicobacter pylori• Epstein Barr vírus• Human papilloma vírus• Hepatitis B eða C• Sveppir sem framl. Aflatoxín• Efni, benzene o.fl.


KrabbameinOrsakir - 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


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 TP53 gene. Of these mutations, 95% can be detected by sequence analysis, which is clinically available.

http://www.geneclinics.org/servlet/access?qry=44&db=genestar&fcn=term&gtreport2=true&id=8888890&key=Po0GXyTXZOt9t&format=frame




KrabbameinOrsakir

Eðlileg afritun DNA bilarDNA-viðgerðar-gen eru stökkbreytt í ristilkrabba

Krabbameinsfrumur eru “ódauðlegar”


Krabbamein

• Líffræðilegir eiginleikar– Frumufjölgun– Stjórnunarprótín bila– Óstöðugleiki í DNA– “Ódauðleiki”– innrás í aðliggjandi vefi– Útrás í æðakerfið– Örva angiogenesis


Krabbamein

• Tvennt ræður mestu um horfur sjúklinga:

– Vefjafræðileg greining• Small cell vs. non small

cell lungnakrabbi• Lymphoma; Hodgkins vs.

non-Hodgkins– Stigun


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


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.

http://www.cellsalive.com/cell_cycle.htm http://www.cellsalive.com/mitosis.htm

Cell cycle

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.

ONCOLOGYPrinciples of chemotherapyElectron

micrographof mitotic

cell

Interphase

Prophase

Telophase

Anaphase

Metaphase

KrabbameinslyfjameðferðStig mítósunar

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


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


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


Krabbamein

• Síðkomnar aukaverkanir lyfjameðferðar– Carcinogenesis

• Myelodysplasia• Ýmis krabbamein


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


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

Alkylerandi Alkylerandi lyflyf

And-efnaskiptaAnd-efnaskiptalyflyf

Mítósu-Mítósu-hemlarhemlar

Tópóísómer-Tópóísómer-AsahemlarAsahemlar(sýklalyf) (sýklalyf)

ÖnnurÖnnur

Flokkun krabbameinslyfja

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


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


Krabbameinslyf

• Lyf sem verka beint á DNA– Alkylerandi lyf (öll forlyf)

• Mechlorethamine• Melphalan• Chlorambucil• Ifosphamide (lengstur T1/2)• Cyclophosphamide• Procarbazine og dacarbazine


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)


CYCLOPHOSPHAMIDECYCLOPHOSPHAMIDE

HEPATICHEPATIC

CYTOCHROMESCYTOCHROMES

P 450P 450

4-OH CYCLOPHOSPHAMIDE4-OH CYCLOPHOSPHAMIDEALDOPHOSPHAMIDEALDOPHOSPHAMIDE

PHOSPHORAMIDEPHOSPHORAMIDE

MUSTARDMUSTARD CYTOTOXICITYCYTOTOXICITYACROLEINACROLEIN

TOXICITYTOXICITY

ALDEHYDEALDEHYDE

DEHYDROGENASEDEHYDROGENASE

4-KETOCYCLOPHOSPHAMIDE4-KETOCYCLOPHOSPHAMIDE

CARBOXYPHOSPHAMIDECARBOXYPHOSPHAMIDEINACTIVATIONINACTIVATION

ACTIVATIONACTIVATION

Krabbameinslyf• Lyf sem verka beint á DNA frh.

– Nitrosourea• Carmustine, lipophil – kjörlyf á æxli í

miðtaugakerfi• Bólga og örmyndun í lungum (isocyanate

niðurbrotsefni)


KrabbameinKrabbamein Ólafur Baldursson

• 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

KrabbameinKrabbamein Ólafur Baldursson

• Lyf sem verka beint á DNA frh.

• Cisplatin– Gjörbreytti meðferð krabbameins í eistum– Nú læknast 70-90%, jafnvel með meinvörp– Áður 5-15 %

Krabbameinslyf• Lyf sem skemma DNA óbeint

– Anthracycline• Doxorubicin, daunorubicin, idarubicin• Mitoxantrone

– Lyf gegn topoisomerasa• Etoposide• Camptothecin

– Ýmis• Bleomycin• Dactinomycin• Mitomycin C



– 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)



– 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



– 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


Krabbameinslyf• Anthracycline

– Aukaverkanir• Myelosuppression• Mucositis• Stomatitis• Mikið drep í húð ef út fyrir æðalegg• Hjartabilun

– Áhættuþættir» Háþrýstingur» Fyrri saga um hjartasjúkdóma



– 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


Krabbameinslyf• Antimetabolitar

– Methotrexate– Pyrimidine analogar

• 5-fluorouracil• Cytarabine• Gemcitabine• Hydroxyurea

– Purine antimetabolitar• Azathioprine• Fludarabine


Purines•Adenine = 6-amino purine

•Guanine = 2-amino-6-oxy purine

Pyrimidines•Uracil = 2,4-dioxy pyrimidine

•Thymine = 2,4-dioxy-5-methyl pyrimidine


– Methotrexate• Blokkar dihydrofolate reductase• Minnkuð framleiðsla á thymidine• Frásog frá meltingarvegi gott en

breytilegt• Útskilið um nýru



– Methotrexate-aukaverkanir• Myelosuppression• Mucositis• interstitial pneumonitis



– 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



– 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



– 5-fluorouracil – Aukaverkanir• Myelosuppression• Mucositis• Niðurgangur• Palmar erythema (ef löng meðferð)• Cerbellar ataxia (sjaldan)



– Aðrir pyrimidine-analogar• Cytarabine (Ara-C)• Gemcitabine• Hydroxyurea

– 100 ára gamalt– Blokkar ribonucleotide reductasa– Aðallega gegn CML– Leucopenia algeng– Almennt stuttvirkt og viðsnúanleg áhrif



– 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


Krabbameinslyf• Tubulin-binding agents

– Vinca alcaloidar• Vincristine• Vinblastine

– Paclitaxel


Krabbameinslyf• Hormón

– Estrogen– Antiestrogen– Aromatasa blokkar– Androgen– Antiandrogen– Progestin– LHRH agonistar– GRH agonistar– Glucocorticoids


Krabbameinslyf• Ýmis lyf

– Interferon– L-asparaginase– Mitotane– Imatinib


Krabbameinslyf• Ýmsar milliverkanir

– Procarbazine blokkar MAO– Allopurinol blokkar 6-mercaptopurine

metabolisma– Barbítúröt og cimetidine auka áhrif

cyclophosphamide– Cisplatín og doxorubicin auka

paclitaxel eitrun– Asparaginase blokkar metabolisma

vinca alkaloids


Krabbameinslyf• Almennar reglur um meðferð

– Leyfa beinmerg að jafna sig (frumufjölgun) eftir myelosuppression áður en næsti skammtur er gefinn nema í illvígu hvítblæði og eitlakrabba

– Varast gjöf lyfja sem hefta starfsemi blóðflagna

– Varast milliverkanir gegnum cytochrome P-450 kerfið

– Stilla skammt í samræmi v. lifrar- eða nýrnabilun

– Beinmergs-cytokín (t.d. GCSF) bæta ekki lifun en eru mjög dýr


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Krabbamein og lyf gegn þeim