title: Combination of local, nonviral IL12 gene therapy and systemic paclitaxel treatment in a metastatic breast cancer model.
abstract: Repeated, local, nonviral IL12 (interleukin-12) gene delivery decreased tumor progression and increased immunogenicity. We combined our IL12 gene delivery with systemic paclitaxel chemotherapy as a treatment for paclitaxel (PCT)-resistant 4T1 subcutaneous mouse mammary carcinomas and PCT-sensitive, immunogenic/nonimmunogenic tumors. We mixed PCT with either a biodegradable polymeric solubilizer, HySolv, or Cremophor EL for bimonthly systemic treatments and injected water-soluble lipopolymer (WSLP)/p2CMVmIL-12 (plasmid encoding IL12 gene) complexes locally every week. We compared treated subcutaneous tumor volume and lung metastasis with controls. HySolv alone performed better compared to Cremophor EL in combination with WSLP/p2CMVmIL-12. We showed inhibition of 4T1 tumor growth and lung metastases in the combined WSLP/p2CMVmIL-12/HySolv group compared to the controls and the paclitaxel-only treated groups. In parallel experiments we also demonstrated additive responses for tumor growth and number of lung metastases within other PCT-sensitive mammary tumor models using this combination strategy. Our combination therapy provides evidence for the efficacy and feasibility of improved drug delivery systems. Local cytokine gene delivery can augment local and systemic chemotherapy without placing the host at risk for further systemic toxicity.
authors.affiliation: Center for Controlled Chemical Delivery, Department of Pharmaceutics and Pharmaceutical Chemistry, University of Utah, 20 South 2030 East, Salt Lake City, UT 84112, USA.
authors.forename: Margit Maria
authors.initials: MM
authors.lastname: Janát-Amsbury
authors.forename: James W
authors.initials: JW
authors.lastname: Yockman
authors.forename: Minhyung
authors.initials: M
authors.lastname: Lee
authors.forename: Steven
authors.initials: S
authors.lastname: Kern
authors.forename: Darin Y
authors.initials: DY
authors.lastname: Furgeson
authors.forename: Malavosklish
authors.initials: M
authors.lastname: Bikram
authors.forename: Sung Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000627:therapeutic use*; D002277:Carcinoma / Q000556:secondary / Q000628:therapy*; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy / Q000379:methods; D005260:Female; D015316:Genetic Therapy / Q000379:methods*; D005990:Glycerol / Q000031:analogs & derivatives* / Q000627:therapeutic use; D018664:Interleukin-12 / Q000235:genetics*; D008055:Lipids / Q000627:therapeutic use; D008175:Lung Neoplasms / Q000556:secondary / Q000628:therapy; D008325:Mammary Neoplasms, Experimental / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D017239:Paclitaxel / Q000627:therapeutic use*; D010957:Plasmids / Q000235:genetics; D011094:Polyethyleneimine / Q000031:analogs & derivatives* / Q000627:therapeutic use
chemical_list: D000972:Antineoplastic Agents, Phytogenic; D008055:Lipids; C438935:poly(ethylenimine)-co-(N-(2-aminoethyl) ethyleneimin)-co-N-(N-cholesteryloxycarbonyl-(2-aminoethyl)ethylenimine); D018664:Interleukin-12; C000515:cremophor EL; D011094:Polyethyleneimine; D017239:Paclitaxel; D005990:Glycerol