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NOVI MODULATOR „MULTI-DRUG“ REZISTENCIJE U TERAPIJI KARCINOMA PLUĆA
NEW MODULATOR OF MULTI-DRUG RESISTANCE IN LUNG CARCINOMA THERAPY
Autor: DANICA KOSANOVID, učenica IV razreda Prve beogradske gimnazije
Regionalni centar za talente Beograd II Mentor: dr MILICA PEŠID, Institut za biološka istraživanja „Siniša
Stankovid“, Beograd
REZIME
MDR (''multi-drug'' rezistencija) je glavna prepreka uspešnoj hemioterapiji tumora. MDR je rezistencija na vedi broj
strukturno i funkcionalno različitih hemioterapeutika i razvija se u toku karcinogeneze (urođena ili de novo
rezistencija) ili u toku hemioterapije (stečena rezistencija). Nove terapeutske strategije za prevazilaženje MDR
ispituju se na in vitro modelima rezistencije. Ova studija je sprovedena na senzitivnoj humanoj delijskoj liniji
karcinoma pluda (NCI-H460) i odgovarajudoj rezistentnoj liniji (NCI-H460/R). Cilj je bio utvrđivanje potencijala
nukleozidnog analoga – sulfinozina ([R,S]-2-amino-9- -D-ribofuranozilpurin-6-sulfinamid) za modulaciju MDR
fenotipa kod NCI-H460/R delija. Sulforodamin B (SRB) testom vijabilnosti pokazano je da sulfinozin (SF) ostvaruje
dozno-zavisan efekat na delijski rast i kod senzitivne, i kod rezistentne linije. IC50 vrednost za SF kod NCI-H460
iznosi 5,3 M, a kod NCI-H460/R - 21,4 M. Pretretman SF-om povedava senzitivnost NCI-H460/R delija na
doksorubicin (DOX) snažnije od dobro-poznatog MDR modulatora - verapamila (VER). Poboljšanje celokupnog
efekta je dobijeno primenom nižih koncentracija SF-a (2,5 M i 5 M) na NCI-H460/R delijama. Efekat SF-a je praden
smanjenjem aktivnosti P-glikoproteina (P-gp), „multi-drug” transportera odgovornog za razvoj rezistencije kod NCI-
H460/R delija. Ovo je utvrđeno na protočnom citometru ispitivanjem akumulacije rodamina 123 (Rho 123) nakon
tretmana SF-om. Dobijeni rezultati pokazuju da SF moduliše MDR kod rezistentne delijske linije karcinoma pluda.
Pored potencijala za reverziju MDR, SF u kombinaciji sa klasičnim citostatikom - DOX može uticati na poboljšanje
efikasnosti hemioterapije.
Ključne reči: MDR („multi-drug” rezistencija), karcinom pluda, sulfinozin, doksorubicin, P-glikoprotein, senzitivizacija
SUMMARY
MDR (''multi-drug resistance'') is a major obstacle to successful cancer treatment. MDR refers as resistance to many
structurally and functionally different drugs and develops during carcinogenesis (natural or de novo resistance) or
during chemotherapy (acquired resistance). New therapeutic strategies to overcome MDR are tested on in vitro
models of resistance. This study was conducted on sensitive human lung cancer cell line (NCI-H460) and its
corresponding resistant line (NCI-H460/R). The aim was to assess the potential of nucleoside analogue - sulfinosine
([R,S]-2-amino-9- -D-ribofuranozylpurine-6-sulfinamide) to modulate MDR phenotype in NCI-H460/R cells.
Sulforodamin B (SRB) cell viability assay showed that SF exerts dose-dependent effect on the cell growth of both,
sensitive and resistant line. IC50 values of SF were 5.3 M and 21.4 M for NCI-H460 and NCI-H460/R, respectively.
The pretreatment with SF increased sensitivity of NCI-H460/R cells to doxorubicin (DOX) stronger than a well-
known MDR modulator - verapamil (VER). The improvement of the overall effect in NCI-H460/R cells was achieved
with lower concentrations of SF (2.5 M and 5 M). The effect of SF was followed by reduced activity of P-
glycoprotein (P-gp), a multi-drug transporter responsible for the development of resistance in NCI-H460/R cells.
This was determined by flow cytometric examination of rhodamine 123 (Rho 123) accumulation after SF treatment.
The results show that SF modulates MDR in resistant lung cancer cell line. Beside its potential for the reversal of
MDR, SF may improve the efficiency of chemotherapy in combination with conventional cytostatic drug – DOX.
Key words: MDR (multi-drug resistance), lung carcinoma, sulfinosine, doxorubicin, P-glycoprotein, sensitization
