2.3 Irinotecano
2.3.5 Topoisomerasi I, geni di riparazione del DNA e regolazione del ciclo
Sappiamo come la topoisomerasi I (TOP I) sia un enzima fondamentale nel ciclo cellulare. Infatti è responsabile dello svolgimento del DNA durante la trascrizione e la replicazione. Il metabolita attivo di CPT-11, SN-38, inibisce la funzione della TOP I tramite la formazione del complesso TOP I / SN-38.
Gli scienziati che studiano le cellule tumorali che presentano resistenza di CPT- 11, hanno trovato che una possibile causa di bassa sensibilità al farmaco può essere associata alla presenza di mutazioni o bassa espressione del gene Top1 (113; 114). Infatti l’impatto che ha la presenza di diverse varianti genetiche di TOP1 può essere causa di resistenza primaria ai farmaci (115).
La conoscenza delle cause della resistenza ai farmaci che portano al fallimento del trattamento con CPT-11, offre l’opportunità di programmare un trattamento più efficace, prevedendo gli effetti della terapia per ogni singolo paziente.
Uno dei fattori molecolari coinvolti nella farmacodinamica di CPT-11 è XRCC1 che svolge un ruolo fondamentale nella riparazione per escissione di base formando un complesso con proteine di riparazione del DNA compresi PARP1 e DNA polimerasi β (116).
Hoskins et al (117) hanno studiato un gruppo di 107 pazienti (europei) con CRC avanzato, trattato con CPT-11. Hanno condotto un’analisi dell’impatto della variante genetica 1196G> A (Arg399Gln) del gene XRCC1 sull’efficacia della terapia con CPT- 11. In tale studio si evince come i pazienti che mostrano una risposta favorevole al trattamento, abbiano più comunemente ha il genotipo 1196GG.
I pazienti omozigoti per un aplotipo XRCC1 (CCGG-G) sono stati, in particolare, coloro che hanno mostrato una risposta oggettiva alla terapia rispetto agli altri pazienti (83% vs 30%, p = 0,02) (117). Una possibile spiegazione di questi risultati
31
è data dal fatto che la presenza dell’allele nella sequenza genica 1196G di XRCC1 è condizionata dalla presenza di arginina nel sequenza 399ARG della proteina XRCC1 che porta ad un DNA con più debole capacità di riparazione, rispetto a quello con la glutamina (399Gln) nella sequenza 1196A. Tuttavia, questi risultati, derivati da studi in vivo, non sono stati confermati in numerosi studi in vitro, che hanno mostrato unanimemente che la presenza di glutammina nel codone 399 è associata con una ridotta capacità di riparazione del DNA.
32
3 CONCLUSIONI E SVILUPPI FUTURI
Concludendo, si può affermare che studi di farmacogenetica potrebbero in futuro essere in grado di predire eventuali risultati della chemioterapia in pazienti affetti da cancro del colon-retto; per esempio, alcuni risultati derivanti da uno studio effettuato sull’irinotecano hanno dimostrato che la riduzione di dosaggio del farmaco per individui omozigoti per il gene UGT1A1*28 ha modificato la risposta farmacologica. Tuttavia, questi risultati sono ancora di difficile interpretazione.
Ci sono indubbiamente vari problemi, tra cui spicca la frequente presenza di un disequilibrio nel collegare con meccanismo causa-conseguenza i vari alleli tra loro, il che rende difficile discernere quale effettivamente sia l’allele da prendere in considerazione per prevedere la cosiddetta “chemio-sensibilità”, ossia l’impatto in negativo che un farmaco chemioterapico potrebbe avere sull’organismo in termini di eventi avversi ed effetti collaterali più o meno gravi.
Subentrano inoltre altre problematiche, tra cui le differenze etniche, che non rendono possibile eseguire un’analisi standardizzata dell’intera popolazione affetta, e anche le differenze inter-etnia che si accumulano con la progressione della differenziazione genetica, e che causano dunque aumento esponenziale dei fenomeni di polimorfismo.
Un’altra problematica riguardante gli studi farmacogenetici, sta nel fatto che alcuni tipi di polimorfismo non predicono soltanto l’efficacia dei chemioterapici, ma anche la prognosi dei pazienti affetti da cancro, in particolar modo per tutto ciò che riguarda i meccanismi riparativi del DNA controllati dai geni: alcuni meccanismi polimorfici di riparazione dell’acido nucleico possono predisporre alla cancerogenesi, ma potrebbero anche migliorare la risposta farmacologica alle terapie una volta che il
33
cancro si sia già sviluppato. Poiché non è facile distinguere i due ambiti, si ha maggiore difficoltà nell’effettuare studi in questo senso.
In generale, è importante sottolineare che attualmente non si ha ancora la possibilità di prevedere con certezza le differenze farmacogenetiche che derivano dai vari tipi di polimorfismo genetico, ma la ricerca mira a sviluppare modelli di pretrattamenti per cancro colorettale che siano predittivi il più possibile, e in cui devono essere considerati sia fattori genetici che non genetici, come per esempio lo stadio del tumore e la tollerabilità di eventuali farmaci a seconda del singolo individuo.
Inoltre, nella maggior parte dei casi, la terapia prevede la somministrazione di farmaci diversi, cosa che rende complicato stabilire quale sia il gruppo di test farmaco genetici da effettuare.
34
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