Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer

Yong Liao, Yiyu Zou, Wei Ya Xia, Mien Chie Hung

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Paclitaxel (Taxol) is a promising frontline chemotherapeutic agent for the treatment of human breast and ovarian cancers. The adenoviral type 5 E1A gene has been tested in multiple clinical trials for its anticancer activity. E1A has also been shown to sensitize paclitaxel-induced killing in E1A-expressing cells. Here, we show that E1A can sensitize paclitaxel-induced apoptosis in breast cancer cells in a gene therapy setting by an orthotopic mammary tumor model. We first showed that expression of E1A enhanced in vitro paclitaxel cytotoxicity, as compared to the control cells. We then compared the therapeutic efficacy of paclitaxel between orthotopic tumor models established with vector-transfected MDA-MB-231 (231-Vect) versus 231-E1A stable cells, using tumor weight and apoptotic index (TUNEL assay) as the parameters. We found paclitaxel was more effective in shrinking tumors and inducing apoptosis in tumor models established with stable 231-E1A cells than the control 231-Vect cells. We also tested whether E1A could directly enhance paclitaxel-induced killing in nude mice, by using a nonviral, surface-protected cationic liposome to deliver E1A gene via the mouse tail vein. We compared the therapeutic effects of E1A gene therapy with or without Taxol chemotherapy in the established orthotopic tumor model of animals inoculated with MDA-MB-231 cells, and found that a combination of systemic E1A gene therapy and paclitaxel chemotherapy significantly enhanced the therapeutic efficacy and dramatically repressed tumor growth (P<.01). In addition, survival rates were significantly higher in animals treated with combination therapy than in the therapeutic control groups (both P<.0001). Thus, the E1A gene therapy indeed enhances the sensitivity of tumor cells to chemotherapy in a gene therapy setting and, the current study provides preclinical data to support combination therapy between E1A gene and chemotherapy for future clinical trials.

Original languageEnglish (US)
Pages (from-to)594-602
Number of pages9
JournalCancer Gene Therapy
Volume11
Issue number9
DOIs
StatePublished - Sep 2004
Externally publishedYes

Fingerprint

Paclitaxel
Heterografts
Breast Neoplasms
Genetic Therapy
Genes
Drug Therapy
Neoplasms
Therapeutics
Clinical Trials
Apoptosis
In Situ Nick-End Labeling
Therapeutic Uses
Tumor Burden
Nude Mice
Liposomes
Ovarian Neoplasms
Tail
Veins
Animal Models
Control Groups

Keywords

  • Breast cancer
  • E1A
  • Gene therapy
  • Nonviral delivery
  • Systemic gene delivery
  • Xenograft

ASJC Scopus subject areas

  • Cancer Research
  • Genetics

Cite this

Enhanced paclitaxel cytotoxicity and prolonged animal survival rate by a nonviral-mediated systemic delivery of E1A gene in orthotopic xenograft human breast cancer. / Liao, Yong; Zou, Yiyu; Xia, Wei Ya; Hung, Mien Chie.

In: Cancer Gene Therapy, Vol. 11, No. 9, 09.2004, p. 594-602.

Research output: Contribution to journalArticle

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