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Table 4 Summary of in vivo studies investigating bisphosphonate effects on macrophages.

From: Tumour macrophages as potential targets of bisphosphonates

Model Bisphosphonate Main Findings Reference
BALB-neut mice with mammary tumour virus (rat c-erb-2-neu/transgene) ZOL 0.1 mg/kg or
PAM 2 mg/kg
5 days a week.
Zol decreased macrophage infiltration into tumour stroma associated with decreased levels of pro-MMP-9 and VEGF Melani C et al [21]
Mammary carcinoma cells implanted in BALB-neutT mice ZOL
100 μM/kg Once a week for 4 weeks, followed by 3 weeks rest, cycle continued.
Impaired TAM recruitment and infiltration into tumour and reduced neo-vascularisation reversal of TAM polarity from pro-tumoural M2 to tumoricidal M1 Coscia et al [83]
HARA-B lung cancer cells implanted in BALB/c nude mice Clodrolip
200 μL or 400 μL Every 3 days for 6 weeks (s.c.).
Reduced TAM infiltration correlated to reduced metastatic spread Hiraoka et al [85]
Human melanoma cell line IIB-MEL-J with or without MCP-1 expression vector. Athymic male NIC-(S)-Nu mice Clodrolip 50 μl or 200 μl (6 mg clodronate per 1 ml ) From day before cell injection and every 5 to 7 days thereafter. Reduced TAMs infiltration correlated to decreased tumour volume and angiogenesis and increased survival Gazzangia et al [86]
F9 teratocarcinoma cells implanted in SV129 female mice Clodrolip, 1 mg/20 g every 4 days. Reduced TAM infiltration.
82% reduction in tumour volume
Zeisberger et al [87]
A673 rhabdomyosarcoma cells into CD-1 nude mice Clodrolip, 1 mg/20 g every 4 days. 93% reduction in TAM
89% reduction in blood vessel density
Zeisberger et al [87]
Metastatic liver cancer Mouse model LM3R or SMMC7721 human hepatocellular cell lines in BALB/c nu/nu mice Clodrolip 100 μg/kg
3 times a week or, ZOL 100 μg/kg 3 times a week and or 30 mg/kg sorafenib.
Reduced TAM infiltration with combination therapy. Correlated with decreased tumour growth, angiogenesis and lung metastasis. ZOL had greater effect than clodrolip Zhang et al [88]
Cervical carcinoma K14-HPV16 transgenic mice ZOL
100 μg
Every day for 3 months.
Decreased MMP-9 expression by TAMs Giraudo et al [72]
Peritoneal macrophage obtained from CBA-J mice injected with AC29 mesothelioma cells Clodronate 200 μl twice over 10 days. Depleted peritoneal macrophages.
Decreased tumour growth
Veltman et al [89]
CBA-J mice injected with AC29 mesothelioma cells ZOL
100 μg/kg s.c.
Every day for 25 days.
Increased myeloid precursors.
Decreased TAMs No significant increase in survival or decrease in tumour burden
Veltman et al [89]