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Protein p16, kodiran genom INK4A, pripada obitelji gena INK4 koja ima ulogu tumor supresora i negativno regulira signalni put pRb-E2F. Genetskim promjenama gena INK4A dolazi do potpune inaktivacije ili do smanjene funkcije proteina p16. Karcinomi glave i vrata su tumori koji nastaju na području usne šupljine, ždrijela, grkljana i žlijezda slinovnica. U 50-70% karcinoma glave i vrata nađena je inaktivacija gena INK4A. U ovom diplomskom radu istraživao sam utjecaj ekspresije proteina p16 u stanicama tumora glave i vrata A253, FaDU i Detroit 562, na ekspresiju ciljnih gena te modulaciju tretmana s kemoterapeuticima. Ustanovio sam da kemoterapeutici induciraju ekspresiju gena INK4A u nekim staničnim linijama te da dodatni tretman s p16 pojačava taj efekt. Prateći ekspresiju ciljnih gena p16 utvrdio sam da se genska i proteinska ekspresija gena BIRC5 (proteina survivin) smanjuje pod utjecajem p16. Genska ekspresija gena BIRC5 se smanjivala nakon tretmanima kemoterapeuticima. Tretman doksorubicinom povećao je gensku ekspresiju E2F1 nekim linijama, dok ju je tretman etopozidom i p16 smanjio. Tretmani kemoterapeuticima i p16 utjecali su na stanični ciklus, uzrokovali oštećenje DNA, te apoptozu i smrt stanica. Kombinirani tretmani s p16 i kemoterapeuticima nisu pokazivali jednoznačne rezultate u staničnim linijama, pa se nije moglo zaključiti ima li p16 ikakav dodatni utjecaj. P16 is a protein coded by the INK4A gene that belongs to INK4 gene family. They have a tumor suppressor role and negatively regulate the pRb-E2F signal pathway. When a genetic mutation appears in INK4A, it leads to inactivation of the protein p16 or its improper function. Head and neck carcinomas can occur in the oral cavity, pharynx, larynx or in the salivary glands. In 50-70% of head and neck cancers the inactivation of INK4A was found. In this graduation thesis I studied the influence of p16 protein expression in head and neck cell lines A253, FaDU and Detroit 562 on the expression of target genes and its effect of the treatment with chemotherapeutic drugs. I found that chemotherapeutics induce expression of INK4A gene in some cell lines and that additional treatment with p16 amplifies that effect. Following the expression of the p16 target genes I found that the protein and gene expression of BIRC5 gene (survivin protein) is lowered under the influence of p16. Gene expression of the BIRC5 gene was lowered with chemotherapeutics treatment. Treatment with doxorubicin increased the E2F1 gene expression in some cell lines, but the treatment with etoposide and p16 lowered E2F1 expression. Treatment with chemotherapeutics and p16 influenced the cell cycle, DNA damage, apoptosis, and cell death. Combined treatment of p16 and chemotherapeutics did not show consistent results in cell lines, so I could not make a conclusion if p16 has any additional influence.

Cilj: U radu je ispitana terapijska vrijednost palijativnog kemoterapijskog programa CCEP (CCNU, klorambucil, etopozid, prednizon) u bolesnika s refraktornim limfomom ili uznapredovanim limfomom u relapsu. Metode: Retrospektivnom analizom prikazani su rezultati liječenja 20 bolesnika u KBC-u Zagreb u 10-godišnjem razdoblju. Liječeno je 8 bolesnika s Hodgkinovim limfomom, 9 s agresivnim ne-Hodgkinovim limfomom (NHL) i 3 bolesnika s indolentnim NHL-om. Rezultati: Bolesnici koji su primili 3 i više ciklusa CCEP-a imali su bolji odgovor na liječenje i dulje preživljenje. Glavni razlog prekida liječenja bila je progresija bolesti te značajna toksičnost. Povoljan odgovor na liječenje ostvaren je u 10 od 20 bolesnika, kod 6 od 20 zabilježena je stabilna bolest, dok je u 4 bolesnika došlo do progresije bolesti. Medijan praćenja iznosio je 11 mjeseci, uz dvogodišnje preživljenje od 30 %. Rasprava i zaključak: CCEP je učinkovit program liječenja koji ima prihvatljivu toksičnost, dobru podnošljivost i niske troškove liječenja. U bolesnika s izrazito nepovoljnom prognozom privremen terapijski uspjeh postiže se u otprilike polovine bolesnika., Aim: Treatment efficacy of CCEP (CCNU, chlorambucil, etopozide and prednisolone), the oral palliative chemotherapy was analyzed in refractory and relapsed lymphoma patients in advanced stages. Methods: In a retrospective study we analyzed 20 patients treated in our institution in 10-year interval. Eight patients were diagnosed with Hodgkin lymphoma, 9 with aggressive non-Hodgkin lymphoma and 3 with indolent lymphoma. Results: Patients receiving ≥3 cycles of CCEP achieved better response rate and longer survival. The progression of the disease was the main reason for discontinuation. Overall response rate was 50 % (10/20 patients); 6/20 patients obtained stable state and 4/20 progressive disease. Median follow-up was 11 months with 30 % of 2-year survival rate. Discussion and conclusion: CCEP is a low-cost and effective chemotherapy with acceptable toxicity and good tolerability. In half of the patients with very adverse prognosis one can expect temporary treatment success.