title: Combination therapy inhibits development and progression of mammary tumours in immunocompetent mice.
abstract: We have determined the effect of combining the chemotherapy agent doxorubicin and the anti-resorptive drug zoledronic acid on the early stages of spontaneous mammary tumour development using the immunocompetent PyMT mouse model that closely mimics human breast cancer development. 6-week-old PyMT mice were treated weekly for 6 weeks with PBS, 2 mg/kg doxorubicin, 100 μg/kg zoledronic acid or doxorubicin followed 24 h later by zoledronic acid (n = 15/group). Untreated, 6-week-old animals were used for comparison of tumour development. Tumour volume, apoptosis and angiogenesis were analysed on H&E, caspase 3, CD31 and CD34 stained histological sections. Proliferation was measured by BrdU incorporation and Ki67 staining and tumour macrophage infiltration assessed by F4/80 immunohistochemistry. Animals treated with doxorubicin followed by zoledronic acid did not develop palpable mammary tumours, whereas in all other treatment groups tumours progressed to late stage adenocarcinomas. Tumours from the combination treatment group were of comparable size to those in 6-week-old untreated animals, remaining pre-malignant with well-differentiated acinar arrangements and with tumour volume only reaching on average 26% of that in the PBS control group. Tumour cell apoptosis and proliferation was significantly reduced compared to control, single agent or untreated 6-week-old mice. Significantly fewer circulating tumour cells were present in animals following sequential treatment compared to all other groups. Combination treatment with doxorubicin followed by zoledronic acid inhibits development and progression of spontaneously occurring mammary tumours.
authors.affiliation: Academic Unit of Clinical Oncology, Medical School, University of Sheffield, Sheffield, UK. P.D.Ottewell@sheffield.ac.uk
authors.forename: Penelope D
authors.initials: PD
authors.lastname: Ottewell
authors.forename: Hannah K
authors.initials: HK
authors.lastname: Brown
authors.forename: Mark
authors.initials: M
authors.lastname: Jones
authors.forename: Thea L
authors.initials: TL
authors.lastname: Rogers
authors.forename: Simon S
authors.initials: SS
authors.lastname: Cross
authors.forename: Nicola J
authors.initials: NJ
authors.lastname: Brown
authors.forename: Robert E
authors.initials: RE
authors.lastname: Coleman
authors.forename: Ingunn
authors.initials: I
authors.lastname: Holen
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage; D049109:Cell Proliferation / Q000187:drug effects; D004164:Diphosphonates / Q000008:administration & dosage; D004195:Disease Models, Animal; D018450:Disease Progression; D004317:Doxorubicin / Q000008:administration & dosage; D005260:Female; D007093:Imidazoles / Q000008:administration & dosage; D007121:Immunocompetence; D008264:Macrophages / Q000187:drug effects; D008297:Male; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000401:mortality / Q000473:pathology; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy; D009367:Neoplasm Staging; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D000077211:Zoledronic Acid
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid; D004317:Doxorubicin