Abstract
Combined chemo-gene therapy is one of the treatment modalities that have attracted extensive research interests; however, there is little information regarding the influence of drug application on gene transfer. This study bridges this gap by examining how chemotherapeutic drugs (teniposide, cis-diamminedichloroplatinum(II) and temozolomide) interfere with polyplex formation and transfection of chitosan-graft-poly(ethylenimine). Our results indicate that the degree of drug interference varies with the mechanism of drug action, with the transgene expression being severely suppressed when the plasmid is co-delivered with cis-diamminedichloroplatinum(II) or teniposide but not temozolomide. In addition, the interference with transfection by drugs varies with different gene/drug co-formulations. This is the first study to evidence that, though combined chemo-gene therapy has therapeutic potential, some chemotherapeutic drugs may reduce the treatment efficiency of gene therapy.
Highlights
Chemotherapy is one of the most widely adopted regimes in cancer treatment, yet its efficiency has been impeded by drug resistance developed in cancer cells [1,2,3,4,5,6]
VM-26 is a potent drug belonging to the class of semisynthetic epipodophyllotoxin glucopyranosides [20]; whereas CDDP is a common drug for treatment of malignancies including bladder, esophageal, head and neck, ovarian, and testicular cancers [21]
As VM-26, CDDP and TMZ are drugs that have been extensively used in chemotherapy, they are ideal models to illustrate how gene/drug coformulation potentially interferes with polyplex formation and transfection
Summary
Chemotherapy is one of the most widely adopted regimes in cancer treatment, yet its efficiency has been impeded by drug resistance developed in cancer cells [1,2,3,4,5,6]. One of the emerging approaches to coping with drug resistance is combined chemo-gene therapy [7,8], which aims at enhancing the action of chemotherapeutic drugs and re-sensitizing drug-resistant cells to chemotherapy. The promising potential of combined chemo-gene therapy was evidenced in vitro by an earlier study in human hepatocellular carcinoma HepG2 cells [9]. The combined treatment was shown to enhance cancer cell death more efficiently than treatment with either the polyplexes or the drug [9]. Transfection of cis-diamminedichloroplatinum(II) (CDDP)-resistant SKOV3/DDP cells with a p53 gene/MDM2-siRNA plasmid was found to PLOS ONE | DOI:10.1371/journal.pone.0126367 May 11, 2015
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