Combination therapy in cancer: effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

Fuso Nerini, Ilaria; Cesca, Marta; Bizzaro, Francesca; Giavazzi, Raffaella

doi:10.1186/s40880-016-0123-1

Cancer Communications

Table 1 Preclinical studies on combinations of anti-vascular endothelial growth factor (VEGF) drugs with conventional therapies, or other therapeutics

From: Combination therapy in cancer: effects of angiogenesis inhibitors on drug pharmacokinetics and pharmacodynamics

Tumor model		Drugs		Treatment schedule		Effects of AI		ST measurement	Ref.
Name	Type	Angiogenesis inhibitor (AI)	Subsequent treatment (ST)	Time of AI before ST	Time of biopsy after ST	Tumor vasculature	Tumor drug uptake	ST measurement	Ref.
NB-1691	Neuroblastoma	Bevacizumab ≈ 8 mg/kg	Topotecan, etoposide	−7 days	1 h	↓ vessel density ↓ permeability ↓ necrosis	= topotecan	HPLC	[20]
				−3 days		↓ vessel density ↓ permeability ↑ perfusion	↑ topotecan =/↑ etoposide
				−1 day		↓ vessel density ↓ permeability ↑ perfusion	=/↑ topotecan ↑ etoposide
				0 day			= topotecan = etoposide
SK-N-AS	Neuroblastoma	Bevacizumab ≈ 8 mg/kg	Topotecan	−7 days	1 h		=/↑ topotecan
				−3 days			↑ topotecan
				−1 day			= topotecan
				0 day			= topotecan
DM443	Melanoma	Bevacizumab 5 mg/kg	Melphalan	−3 days	1 day	↓ perfusion/permeability = vessel density	↑ melphalan	IHC of DNA-melphalan adduct	[34]
DM738	Melanoma	Bevacizumab 5 mg/kg	Melphalan	−3 days	1 day	↓ perfusion/permeability = vessel density	↑ melphalan	IHC of DNA-melphalan adduct	[34]
SAS	Head and neck cancer	Bevacizumab ≈ 10 mg/kg	BPA	−7 days	1 h		= BPA	PGA	[66]
				−3 days		↓ vessel density	= BPA
				−1 day		↑ perfusion/permeability	↑ BPA
				−0.5 day			↑ BPA
HCCLM3	Hepatic cancer	Bevacizumab 5 mg/kg	Doxorubicin	−7 days	1 h	↓ vessel density	= doxorubicin	HPLC	[67]
				−5 days			↑ doxorubicin
				−3 days			↑ doxorubicin
				−1 day			= doxorubicin
				0 day			= doxorubicin
MX-1	Breast cancer	Bevacizumab 5 mg/kg	Paclitaxel	−1 h	2 days	↓ perfusion/permeability	↑ paclitaxel	HPLC	[68]
A549	Lung cancer	Bevacizumab 5 mg/kg	Paclitaxel	−1 h	2 days	↓ perfusion/permeability	↑ paclitaxel	HPLC	[68]
OSC-19	Oral squamos cancer	Bevacizumab ≈ 4 mg/kg	Cetuximab	−3 days	From 1 to 13 days	↑ pericyte coverage	↑ cetuximab	FM	[70]
SCC-1	Oral squamos cancer	Bevacizumab ≈ 4 mg/kg	Cetuximab	−3 days	From 1 to 13 days		↑ cetuximab	FM	[70]
U87MG	Glioblastoma	Bevacizumab 10 mg/kg	Temozolomide, irinotecan	−7 days	1 h		=/↑ temozolomide =/↑ irinotecan	HPLC	[71]
U87MG	Glioblastoma	Bevacizumab 10 mg/kg	Temozolomide, irinotecan	0 day	1 h		=/↑ temozolomide =/↑ irinotecan	HPLC	[71]
KPL4	Breast cancer	Bevacizumab 10 mg/kg	Trastuzumab	−7 days	6 h	↓ vessel density	↓ trastuzumab	multispectral ultra FM	[72]
				−3 days		↓ vessel density	↓ trastuzumab
				−1 day		↓ vessel density	↓ trastuzumab
KPL4	Breast cancer	B20.4.1 10 mg/kg	Trastuzumab	−1 day	From 1 to 7 days	↓ vessel density ↓ perfusion	↓ trastuzumab	SPECT	[73]
MMTV-HER2 Fo5	Breast cancer	B20.4.1 10 mg/kg	Trastuzumab	−1 day	From 1 to 7 days		↓ trastuzumab	SPECT	[73]
SUM149	Colon cancer	Bevacizumab 10 mg/kg	Cetuximab, R1507 (Ab a IGF1R)	−4 days	3 days	↓ vessel density	↓ R1507 ↓ cetuximab	SPECT	[74]
SKBR3	Breast cancer	Bevacizumab 10 mg/kg	R1507 (Ab a IGF1R)	−4 days	3 days		↓ R1507	SPECT	[74]
MDA-MB-435	Breast cancer	A461 1 mg/kg	Cisplatin + 5-FU	−1 day	1 h	↓ perfusion/permeability ↓ vessel density ↑ pericyte coverage	↓ cisplatin = 5-FU	ICP-AES (cisplatin) HPLC (5-FU)	75]
SKOV-3	Ovarian cancer	Bevacizumab 5 mg/kg	Trastuzumab	−1, 2, and 5 days	1 and 6 days		↓ trastuzumab	PET	[76]
OE19	Esophageal cancer	Bevacizumab 5 mg/kg	Trastuzumab	−1, 2, and 5 days	1 and 6 days		↓ trastuzumab	PET	[76]
A2780-1A9	Ovarian cancer	Bevacizumab ≈ 6 mg/kg	Paclitaxel	−5 and −1 days	From 0.25 h to 3 days	↓ vessel diameter ↓ perfusion/permeability ↓ necrosis	↓ paclitaxel	HPLC MALDI	[77]
IGROV1	Ovarian cancer	Bevacizumab ≈6 mg/kg	Paclitaxel	−5 and −1 days	6 h	↓ vessel diameter	= paclitaxel
HT-29	Colon cancer	Bevacizumab ≈6 mg/kg	Paclitaxel	−5 and −1 days	6 h	↓ vessel density	= paclitaxel
HT29	Colon cancer	A461 ≈ 8 mg/kg	Irinotecan	−7 and −3 days	1 h	↓ vessel number/diameter ↑ perfusion/permeability = necrosis	=/↑ irinotecan = SN-38 metabolite	HPLC	[78]

= equal; ↓ reduction; ↑ increase; =/↓ no significant reduction; =/↑ no significant increase; HPLC high performance liquid chromatography; IHC immunohistochemistry; BPA p-boronophenylalanine; PGA prompt γ-ray spectrometry; FM fluorescence microscopy; SPECT single photon emission computerized tomography; ICP-AES inductively coupled plasma atomic emission spectrometry; 5-FU 5-fluorouracil; PET positron emission tomography; MALDI matrix-assisted laser desorption/ionization

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