Gene expression in intrahepatic tumors through DNA recombination by a replication-activated adenovirus vector

Huang, Xiqiang; Lieber, André; Tang, Zhao You; Lawrence, Theodore S.; Moyer, Mary Pat; Zhang, Ming

doi:10.1038/sj.cgt.7700719

Cited by 1 publication

(1 citation statement)

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“…Ad vectors possess advantages for in vivo gene transfer into tumors including their superior in vivo gene transfer efficiency of both dividing and non-dividing cells after systemic or intratumoral administration. [25][26][27] Ad vectors are also being used to deliver prodrug-activating enzymes into tumors in clinical trials. 28 Because it is difficult to transduce all cancer cells in a tumor, we also investigated if tumor-located expression of membrane-tethered bG could sensitize untransduced bystander cancer cells to SN-38G.…”

Section: Introductionmentioning

confidence: 99%

Enhancement of CPT-11 antitumor activity by adenovirus-mediated expression of β–glucuronidase in tumors

Huang

Prijovich

et al. 2011

Cancer Gene Ther

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CPT-11 is a clinically important prodrug that requires conversion into the active metabolite SN-38, a potent topoisomerase I poison, for antitumor activity. However, SN-38 is rapidly metabolized to the inactive SN-38 glucuronide (SN-38G) in the liver, which reduces the amount of SN-38 available for killing cancer cells. Here, we investigated if local expression of b-glucuronidase (bG) on cancer cells to catalytically convert SN38G to SN38 could enhance the antitumor activity of CPT-11. bG was tethered on the plasma membrane of three different human cancer cell lines: human colon carcinoma (LS174T), lung adenocarcinoma (CL1-5) and bladder carcinoma (EJ). Surface b-glucuronidase-expressing cells were 20 to 80-fold more sensitive to SN-38G than the parental cells. Intravenous CPT-11 produced significantly greater suppression of CL1-5 and LS174 T tumors that expressed bG as compared with unmodified tumors. Furthermore, an adenoviral vector expressing membrane-tethered bG (Ad.bG) increased the sensitivity of cancer cells to SN-38G even at multiplicity of infections as low as 0.16, indicating bystander killing of non-transduced cancer cells. Importantly, intratumoral injection of Ad.bG significantly enhanced the in vivo antitumor activity of CPT-11 as compared with treatment with CPT-11 or Ad vectors alone. This study shows that Ad.bG has potential to boost the therapeutic index of CPT-11.

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