Abstract
Irinotecan hydrochloride, tseem paub los ntawm nws lub npe npe Camptosar® lossis CPT -11, yog ib qho khoom siv hluav taws xob ib nrab ntawm lub ntuj alkaloid camptothecin. Raws li topoisomerase I inhibitor, irinotecan tau tshwm sim los ua lub hauv paus hauv kev kho mob ntawm ntau yam qog nqaij hlav, tshwj xeeb tshaj yog mob qog noj ntshav. Kab lus no muab cov ntsiab lus tob ntawm irinotecan cov qauv tshuaj, cov txheej txheem ntawm kev ua, pharmacokinetics, kev kho mob zoo, thiab kev nyab xeeb profile. Tsis tas li ntawd, peb tham txog kev tshawb fawb tsis tu ncua tshawb nrhiav cov qauv tshiab, kev kho mob sib xyaw ua ke, thiab muaj peev xwm biomarkers los txhim kho irinotecan's antitumor cov teebmeem thiab txo qis toxicity.
Taw qhia
Mob qog noj ntshav, kab mob nyuaj thiab ntau yam, ua rau muaj kev nyuaj siab rau ntiaj teb kev noj qab haus huv. Hauv kaum xyoo tsis ntev los no, kev nce qib tseem ceeb tau ua hauv kev kho mob qog noj ntshav, nrog rau kev kho tshuaj khomob ua lub luag haujlwm tseem ceeb. Ntawm cov kws khomob ntau yam tshuaj khomob, irinotecan hydrochloride sawv tawm rau nws cov txheej txheem tshwj xeeb ntawm kev ua haujlwm thiab ua pov thawj ua tau zoo tiv thaiv ntau yam kabmob. Qhov kev tshuaj xyuas no yog txhawm rau txheeb xyuas qhov kev nkag siab tam sim no ntawm irinotecan's anticancer zog, qhia txog nws qhov tseem ceeb hauv kev kho mob thiab cov lus qhia yav tom ntej.
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Chemistry thiab Mechanism of Action
Irinotecan hydrochloride yog ib qho dej-soluble prodrug uas dhau los ua cov metabolism hauv hepatic los tsim nws cov metabolite nquag, 7-ethyl-10-hydroxycamptothecin (SN-38). SN-38, lub zog inhibitor ntawm topoisomerase I, exerts nws cytotoxic teebmeem los ntawm stabilizing covalent topoisomerase I-DNA complex, ua rau DNA strand so thiab tom qab cell tuag. Cov txheej txheem no yog qhov txawv ntawm cov tshuaj DNA-kev puas tsuaj, ua rau irinotecan qhov kev xaiv zoo rau kev kov yeej cov tshuaj tiv thaiv.
Pharmacokinetics
Irinotecan yog siv rau hauv cov hlab ntsha thiab ua rau cov metabolism hauv siab, feem ntau yog los ntawm cytochrome P450 enzyme CYP3A4, tsim SN-38 thiab ob lub metabolites tsis ua haujlwm, APC thiab SN-38G. SN-38, active metabolite, yog ntxiv glucuronidated los ntawm uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) los ua SN-38G, uas yog tawm hauv cov kua tsib thiab zis. Lub complex pharmacokinetics ntawm irinotecan, tshwj xeeb tshaj yog tsim thiab tshem tawm ntawm SN-38, ho cuam tshuam nws cov kev kho mob Performance index thiab toxicity profile.
Kev siv tshuaj kho mob
Irinotecan tau kawm ntau thiab pom zoo rau kev kho mob ntawm ntau yam qog nqaij hlav, nrog rau mob qog nqaij hlav hauv plab (CRC) yog nws thawj qhov qhia. Ua ke nrog 5-fluorouracil (5-FU) thiab leucovorin (LV), irinotecan tsim cov pob txha ntawm ntau cov tshuaj kho mob, suav nrog FOLFIRI (5-FU/LV/irinotecan) thiab IFL (irinotecan). /5-FU/LV), uas tau ua kom pom kev ua kom muaj sia nyob zoo dua piv rau 5-FU/LV ib leeg.
- Kab mob qog noj ntshav: Nyob rau hauv metastatic CRC, irinotecan-raws li kev tswj hwm tau tsim los ua thawj kab thiab kev cawm siav, muab cov txiaj ntsig tseem ceeb ntawm kev ciaj sia.
- Mob ntsws cancer: Txawm hais tias tsis yog thawj qhov qhia, irinotecan tau pom cov txiaj ntsig tau zoo hauv kev ua ke nrog lwm tus neeg ua haujlwm rau xaiv cov neeg mob uas tsis yog mob qog noj ntshav me me (NSCLC).
- Lwm cov qog nqaij hlav: Cov kev tshawb fawb txwv tau tshawb nrhiav irinotecan qhov ua tau zoo hauv zes qe menyuam, qog noj ntshav, thiab mob qog noj ntshav, thiab lwm yam, nrog rau ntau qib ntawm kev ua tiav.
Kev nyab xeeb thiab toxicity
Txawm hais tias nws muaj peev xwm kho tau, irinotecan cuam tshuam nrog cov tshuaj lom neeg tshwj xeeb, tshwj xeeb tshaj yog raws plab thiab neutropenia. Qhov hnyav ntawm cov kev mob tshwm sim no cuam tshuam los ntawm tus neeg hloov pauv hauv irinotecan metabolism, tshwj xeeb tshaj yog UGT1A1 genotype. Cov neeg mob uas muaj qee yam UGT1A1 polymorphisms, xws li28/28, muaj kev pheej hmoo ntau dua thiab muaj peev xwm ua rau mob raws plab.
Lwm yam teebmeem tshwm sim muaj xws li xeev siab, ntuav, alopecia, thiab qaug zog. Kev txhim kho ntawm kev txhawb nqa kev ntsuas, suav nrog kev siv loperamide rau kev tiv thaiv kab mob raws plab thiab kev loj hlob ntawm neutropenia, tau txhim kho qhov ua tau zoo ntawm kev kho mob irinotecan-based.
Kev tshawb fawb tam sim no thiab cov lus qhia yav tom ntej
Kev tshawb fawb tam sim no
Cov kws tshawb fawb tab tom tshawb nrhiav cov kev hloov kho-tso tawm cov qauv thiab cov phiaj xwm xa khoom los txhim kho irinotecan qhov ntsuas kho thiab txo cov tshuaj lom. Piv txwv li, nanoparticle-encapsulated irinotecan tau qhia txog kev txhim kho tshuaj ruaj khov thiab qog nqaij hlav hauv cov kev tshawb fawb ua ntej.
Muab irinotecan cov txheej txheem tshwj xeeb ntawm kev ua, nws yog ib tus khub txaus nyiam rau kev sib xyaw ua ke. Kev sim tsis tu ncua yog tshawb xyuas irinotecan ua ke nrog kev siv tshuaj tiv thaiv kab mob, kev kho mob, thiab lwm yam tshuaj khomob los txhim kho cov lus teb thiab ua kom muaj sia nyob ntev.
Txhawm rau txhim kho qhov ua tau zoo thiab txo cov kev mob tshwm sim ntawm CPT-11, cov kws tshawb fawb tau tsim ntau yam qauv, xws li liposomal irinotecan. Liposomal formulations tau pom tias muaj kev ruaj ntseg ntawm cov tshuaj, txhim kho pharmacokinetics, thiab muaj peev xwm ua kom pom cov qog zoo dua.
Piv txwv li, cov kev tshawb fawb tau tshawb xyuas kev siv CPT-11- loaded liposomes nrog rau lwm yam tshuaj khomob los yog cov hom phiaj kho mob rau kev kho mob qog nqaij hlav hauv plab thiab lwm yam mob.
CPT-11 paub tias ua rau muaj kev phiv loj heev, suav nrog neutropenia (cov qe ntshav dawb tsawg) thiab raws plab qeeb. Kev tshawb fawb tsis tu ncua yog txhawm rau txo cov teebmeem tsis zoo no los ntawm kev ua kom zoo dua cov sijhawm noj tshuaj, kev sib xyaw ua ke, thiab cov qauv tshiab.
Muaj ntau qhov kev sim tshuaj tsis tu ncua uas tshawb xyuas qhov ua tau zoo thiab kev nyab xeeb ntawm CPT-11, ob qho tib si raws li kev kho mob monotherapy thiab ua ke nrog lwm tus neeg ua haujlwm, rau ntau yam kab mob qog noj ntshav. Cov kev sim no nyob rau theem sib txawv, suav nrog Phase I, II, thiab III, thiab koom nrog cov neeg mob uas mob qog noj ntshav lossis mob qog noj ntshav.
Cov lus qhia yav tom ntej
Biomarker-Guided Therapy
Kev txheeb xyuas cov biomarkers uas kwv yees cov lus teb rau CPT-11- cov kev kho mob raws li tuaj yeem pab xaiv cov neeg mob uas feem ntau yuav tau txais txiaj ntsig los ntawm cov kev kho mob no, yog li kev kho mob cancer tus kheej.
Mechanistic Studies
Kev nkag siab tob dua ntawm cov txheej txheem molecular hauv qab CPT-11 cov haujlwm antitumor thiab nws cov kev cuam tshuam nrog lwm cov tshuaj lossis cov txheej txheem ntawm tes yuav ua rau kev tshawb pom cov hom phiaj kho mob tshiab thiab cov tswv yim.
Xaus
Irinotecan hydrochloride, semi-synthetic camptothecin derivative, tuav cov lus cog tseg tseem ceeb hauv thaj tsam ntawm kev tshawb fawb tshuaj tiv thaiv kab mob. Nws cov lus qhia tau hloov kho qhov chaw kho mob rau ntau yam ntawm cov qog nqaij hlav, tshwj xeeb tshaj yog mob qog noj ntshav hauv plab, qhov twg nws yog lub hauv paus ntawm cov tshuaj kho mob. Cov tshuaj tshwj xeeb cov txheej txheem ntawm kev ua, inhibiting topoisomerase I, ib qho enzyme tseem ceeb rau DNA replication thiab kho, cuam tshuam cov qog nqaij hlav qog nqaij hlav ntawm theem tseem ceeb.
Irinotecan qhov ua tau zoo yog los ntawm nws lub peev xwm los txhawm rau faib cov qog hlwb sai sai, thaum sparing cov ntaub so ntswg uas tsis muaj kev loj hlob mus rau ntau dua, yog li txo cov kab mob toxicity. Qhov tshwj xeeb no txhim kho qhov ntsuas kev kho mob, tso cai rau cov koob tshuaj ntau dua rau kev tswj hwm cov kev mob tshwm sim. Nws cov dej num hauv ob qho tib si hauv lub cev thiab hauv cov qog microenvironment tau ua qhov tseem ceeb hauv kev txhim kho cov txiaj ntsig ntawm tus neeg mob, suav nrog kev muaj sia nyob ntev thiab txhim kho lub neej zoo.
Ntxiv mus, irinotecan txoj kev kho mob tau zoo tau ua rau muaj kev tshawb nrhiav ntxiv rau nws txoj kev siv hauv kev kho mob ua ke, feem ntau nrog rau lwm cov kws khomob lossis cov kws khomob. Cov kev sib xyaw ua ke no siv cov txiaj ntsig zoo sib xws, txhawm rau kov yeej cov tshuaj tiv thaiv thiab nthuav dav cov kab mob ntawm cov qog ua haujlwm.
Hauv kev xaus, irinotecan hydrochloride sawv cev rau kev nce qib tseem ceeb hauv cov tswv yim antitumor, muab kev kho mob zoo thiab muaj txiaj ntsig zoo rau ntau tus neeg mob qog noj ntshav. Nws txuas ntxiv kev tshawb nrhiav thiab kev txhim kho tuav lub peev xwm los txhim kho kev tswj xyuas mob qog noj ntshav thiab thaum kawg txhim kho cov neeg mob tau txais txiaj ntsig thoob ntiaj teb.