Aerosol Gemcitabine after Amputation Inhibits Osteosarcoma Lung Metastases but Not Wound Healing

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Abstract

Background. In newly diagnosed osteosarcoma (OS) patients, the time between surgery and resumption of chemotherapy is 2-7 weeks. Delays > 16 days are associated with increased risk of relapse and decreased overall survival. Identifying an effective therapy that can be used postoperatively may prevent relapse. We investigated whether aerosol gemcitabine (GCB) initiated after tumor resection inhibited the growth of OS lung metastases without affecting the wound-healing process. Methods. Mice were injected intratibially with OS cells. Amputation was performed when the tumor reached 1.5 cm. Full-thickness excisional wounds were also made on the dorsal skin and tail. Aerosol GCB or PBS was initiated 48 hours after amputation (3 times/week for 3 weeks). Wound sections were evaluated by immunohistochemistry for Ki-67 (proliferation), CD31 (vessels), VEGF, IL-10, bFGF, mast cells, macrophages, and M1/M2 macrophage ratios. The lungs were analyzed for macro- and micrometastases. Results. Aerosol GCB inhibited the growth of the lung metastases but had no effect on the 3 phases of wound healing in the dorsal skin, tail, or bone. Production of cytokines at the wound sites was the same. Conclusion. These data indicate that initiating aerosol GCB postoperatively may kill residual lung metastases thereby preventing relapse and improve survival.

Figures

  • Figure 1: Serum GCB levels following intraperitoneal (i.p.) and aerosol GCB. Mice were treated with 1mg/kg GCB given i.p. or by aerosol administration. Blood was collected at various times following administration, and serum GCB levels were quantified. Mice treated with aerosol GCB had significantly lower serum levels (P< 0.05).
  • Figure 2: Continued.
  • Figure 2: Aerosol GCB inhibited lung metastases but had no effect on wound healing in the tail, dorsal skin, or bone. (a) Representative appearance of the dorsal wound on days 1 and 10 in the mice treated with aerosol PBS (top row) or aerosol GCB (bottom row). (b))e areas of each wound in the aerosol PBS and aerosol GCB groups were measured 1, 4, 7, and 10 days after treatment (P> 0.05 for each group). (c) Representative H&E sections from the wounded tail, dorsal skin, and postamputation area 7 days following wounding. (d–f ) Aerosol GCB inhibited the growth of osteosarcoma lung metastases as assessed visually (d), by the lung weight (e), and by the mean number of lung metastases (f ) (P< 0.01).
  • Figure 3: Effect of aerosol GCB on cell proliferation and fibroblast numbers associated with wound healing.)e dorsal and tail skin wounds from themice treated with aerosol PBS or aerosol GCBwere examined on day 7. (a) Cell proliferation was assessed using Ki67. (b) Fibroblast numbers were assessed using anti-fibroblast antibody.)e positive areas were quantified by SimplePCI groups obtained from five h.p.f areas and compared using Student’s t-test. P> 0.05 for all graphs.
  • Figure 4: Effect of aerosol GCB on mast cell and macrophage infiltration andM1/M2 wound content.)e dorsal and tail skin wounds from themice treated with aerosol PBS or aerosol GCBwere examined on day 7 for (a) mast cells using toluidine blue and (b) macrophage content using F4/80 antibody. (c) M1macrophages were identified by anti-iNOS; (d) M2macrophages were identified using anti-mannose receptor. )e positive areas were quantified by SimplePCI groups obtained from five h.p.f areas and compared using Student’s t-test. P> 0.05 for all graphs.
  • Figure 5: Effect of aerosol GCB on CD31 and VEGFR in the wound area.)e dorsal and tail skin wounds from the mice treated with aerosol PBS or aerosol GCB were examined on day 7 using (a) anti-CD31 or (b) anti-VEGFR )e positive areas were quantified by SimplePCI groups obtained from five h.p.f areas and compared using Student’s t-test. P> 0.05 for all graphs.
  • Figure 6: Effect of aerosol GCB on IL-10 and FGF-2 (bFGF) in the wound. )e dorsal and tail skin wounds from the mice treated with aerosol PBS or aerosol GCB were examined on day 7 using (a) anti-IL-10 or (b) anti-FGF-2.)e positive areas were quantified by SimplePCI groups obtained from five h.p.f areas and compared using Student’s t-test. P> 0.05 for all graphs.
  • Figure 7: Aerosol GCB did not affect bone healing following amputation. Representative sections of immunohistochemistry of the mice 14 days after amputation for fibroblasts, CD31, VEGFR-2, FGF-2 (bFGF), and IL-10.

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APA

Kleinerman, E. S., Yu, L., Dao, J., Hayes-Jordan, A. A., Lindsey, B., Kawedia, J. D., … Gordon, N. (2018). Aerosol Gemcitabine after Amputation Inhibits Osteosarcoma Lung Metastases but Not Wound Healing. Sarcoma, 2018. https://doi.org/10.1155/2018/3143096

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