Title : An improved human carboxylesterase for enzyme\/prodrug therapy with CPT-11 - Wierdl_2008_Cancer.Gene.Ther_15_183 |
Author(s) : Wierdl M , Tsurkan L , Hyatt JL , Edwards CC , Hatfield MJ , Morton CL , Houghton PJ , Danks MK , Redinbo MR , Potter PM |
Ref : Cancer Gene Therapy , 15 :183 , 2008 |
Abstract :
CPT-11 is a potent antitumor agent that is activated by carboxylesterases (CE) and intracellular expression of CEs that can activate the drug results in increased cytotoxicity to the drug. As activation of CPT-11 (irinotecan-7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxycamptothecin) by human CEs is relatively inefficient, we have developed enzyme/prodrug therapy approaches based on the CE/CPT-11 combination using a rabbit liver CE (rCE). However, the in vivo application of this technology may be hampered by the development of an immune response to rCE. Therefore, we have developed a mutant human CE (hCE1m6), based on the human liver CE hCE1, that can activate CPT-11 approximately 70-fold more efficiently than the wild-type protein and can be expressed at high levels in mammalian cells. Indeed, adenoviral-mediated delivery of hCE1m6 with human tumor cells resulted in up to a 670-fold reduction in the IC(50) value for CPT-11, as compared to cells transduced with vector control virus. Furthermore, xenograft studies with human tumors expressing hCE1m6 confirm the ability of this enzyme to activate CPT-11 in vivo and induce antitumor activity. We propose that this enzyme should likely be less immunogenic than rCE and would be suitable for the in vivo application of CE/CPT-11 enzyme/prodrug therapy. |
PubMedSearch : Wierdl_2008_Cancer.Gene.Ther_15_183 |
PubMedID: 18188187 |
Wierdl M, Tsurkan L, Hyatt JL, Edwards CC, Hatfield MJ, Morton CL, Houghton PJ, Danks MK, Redinbo MR, Potter PM (2008)
An improved human carboxylesterase for enzyme\/prodrug therapy with CPT-11
Cancer Gene Therapy
15 :183
Wierdl M, Tsurkan L, Hyatt JL, Edwards CC, Hatfield MJ, Morton CL, Houghton PJ, Danks MK, Redinbo MR, Potter PM (2008)
Cancer Gene Therapy
15 :183