Paclitaxel Decreases the Interstitial Fluid Pressure and Improves Oxygenation in Breast Cancers in Patients Treated With Neoadjuvant Chemotherapy: Clinical Implications

Taghian, Alphonse G.; Abi‐Raad, Rita; Assaad, Sherif; Casty, Adrian; Ancukiewicz, Marek; Yeh, Edmund; Molokhia, Peryhan; Attia, Khaled; Sullivan, Timothy; Kuter, Irene; Boucher, Yves; Powell, Simon N.

doi:10.1200/jco.2005.08.119

Cited by 181 publications

(129 citation statements)

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“…Furthermore, tumour hypoxia is associated with poor overall and disease-free survival, greater disease recurrence and less locoregional control in head and neck cancer, cervical carcinoma and soft-tissue sarcomas (Brizel et al, 1999;Birner et al, 2000;Bachtiary et al, 2003;Harrison and Blackwell, 2004). In addition, a statistically significant relationship between IFP and tumour oxygenation has been demonstrated in breast cancer patients (Taghian et al, 2005). In an animal model of metastatic prostate cancer, animals treated with Imatinib plus paclitaxel had significantly smaller tumours, and fewer bone and lymph node metastasis than mice treated with placebo or paclitaxel alone (Uehara et al, 2003).…”

Section: Discussionmentioning

confidence: 99%

“…Comparison of IFP and pO 2 measurements in patients with cervical cancer demonstrate that IFP is a stronger predictor than hypoxia for pelvic recurrence and disease-free survival (Milosevic et al, 2004). Although the relationship between IFP and pO 2 is not fully understood, hypoxia is believed to be associated with an increased IFP in solid tumours (Taghian et al, 2005).…”

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confidence: 99%

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Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation

et al. 2006

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Elevated intratumoral interstitial fluid pressure (IFP) and tumour hypoxia are independent predictive factors for poor survival and poor treatment response in cancer patients. However, the relationship between IFP and tumour hypoxia has not yet been clearly established. Preclinical studies have shown that lowering IFP improves treatment response to cytotoxic therapy. Interstitial fluid pressure can be reduced by inhibition of phosphorylated platelet-derived growth factor receptor-b (p-PDGFR-b), a tyrosine kinase receptor frequently overexpressed in cancer stroma, and/or by inhibition of VEGF, a growth factor commonly overexpressed in tumours overexpressing p-PDGFR-b. We hypothesised that Imatinib, a specific PDGFR-b inhibitor will, in addition to p-PDGFR-b inhibition, downregulate VEGF, decrease IFP and improve tumour oxygenation. A549 human lung adenocarcinoma xenografts overexpressing PDGFR-b were grown in nude mice. Tumour-bearing animals were randomised to control and treatment groups (Imatinib 50 mg kg À1 via gavage for 4 days). Interstitial fluid pressure was measured in both groups before and after treatment. EF5, a hypoxia marker, was administered 3 h before being killed. Tumours were sectioned and stained for p-PDGFR-b, VEGF and EF5 binding. Stained sections were viewed with a fluorescence microscope and image analysis was performed. Imatinib treatment resulted in significant reduction of p-PDGFR-b, VEGF and IFP. Tumour oxygenation was also significantly improved. This study shows that p-PDGFR-b-overexpressing tumours can be effectively treated with Imatinib to decrease tumour IFP. Importantly, this is the first study demonstrating that Imatinib treatment improves tumour oxygenation and downregulates tumour VEGF expression.

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confidence: 99%

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Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation

et al. 2006

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“…Cancer cells may experience physical forces in a variety of settings. Cancers growing rapidly against a constraining stroma may exhibit increased interstitial pressures (15,16), whereas metastasizing tumor cells experience pressure and shear during passage through the lymphatics or vasculature. Perioperatively, cancer cells are commonly shed from tumors into the surgical site or the venous circulation during procedures, and the presence of free tumor cells on the outside of the surgical specimen correlates adversely with prognosis for colon cancers (17).…”

Section: Discussionmentioning

confidence: 99%

An Intracellular Signal Pathway That Regulates Cancer Cell Adhesion in Response to Extracellular Forces

Basson

2008

Cancer Research

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Increasing evidence suggests that tumor cells can regulate their own adhesion via intracellular signals that modulate integrin binding affinity. Although the full pathway has not yet been elucidated, the effects of pressure seem likely to require cytoskeletal mechanosensing, Src, phosphatidylinositol 3-kinase, focal adhesion kinase, and Akt-1 activation. Ultimately, activated focal adhesion kinase accumulates at the membrane in association with B 1

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“…In one study, IFP was used as a prognostic factor and this showed that it was the single best indicator of survival for patients with cancer of the cervix where a high IFP was associated with a poor prognosis (25). More recently, it has been shown that Avastin, the vascular endothelial growth factor A antibody, and paclitaxel could lower the IFP of renal and breast tumors, respectively (26,27). A demonstration of a correlation between changes in tumor growth and IFP in the same tumor would suggest that IFP could be used as a surrogate biomarker of response.…”

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confidence: 99%

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

Ferretti

Allegrini

O’Reilly

et al. 2005

Clinical Cancer Research

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Purpose: Evaluation of vascular disruptive activity in orthotopic models as potential surrogate biomarkers of tumor response to the microtubule-stabilizing agent patupilone. Experimental Design: Mice bearing metastatic B16/BL6 melanoma and rats bearing mammary BN472 tumors received vehicle or efficacious patupilone doses (4 and 0.8-1.5 mg/kg i.v., respectively). Tumor vascularity assessment by dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and interstitial fluid pressure (IFP) occurred at baseline, 2 days (mice and rats), and 6 days (rats) after treatment and were compared with histologic measurements and correlated with tumor response.Results: In B16/BL6 metastases, patupilone (4 mg/kg) induced a 21 F 5% decrease (P < 0.001) in tumor blood volume and a 32 F 15% decrease (P = 0.02) in IFP after 2 days and reduced tumor growth and vessel density (>42%) after 2 weeks (P V 0.014). Patupilone dose-dependently inhibited BN472 tumor growth (day 6) and reduced IFP on days 2 and 6 (À21% to À70%), and the percentage change in IFP correlated (P < 0.01) with the change in tumor volume. In both models, histology and vascular casts confirmed decreases in tumor blood volume. One patupilone (0.8 mg/kg) administration decreased (P < 0.01) tumor IFP (54 F 4%), tumor blood volume (50 F 6%), and vessel diameter (40 F 11%) by day 6 but not the apparent diffusion coefficient, whereas histology showed that apoptosis was increased 2.4-fold and necrosis was unchanged.Apoptosis correlated negatively (P < 0.001) with IFP, tumor blood volume, and tumor volume, whereas tumor blood volume and IFP were correlated positively (P = 0.0005). Conclusions: Vascular disruptive effects of patupilone were detected in situ using dynamic contrast-enhanced or dynamic susceptibility contrast magnetic resonance imaging and IFP. Changes in IFP preceded and correlated with tumor response, suggesting that IFP may be a surrogate biomarker for patupilone efficacy.

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Paclitaxel Decreases the Interstitial Fluid Pressure and Improves Oxygenation in Breast Cancers in Patients Treated With Neoadjuvant Chemotherapy: Clinical Implications

Abstract: Paclitaxel significantly decreased the IFP and increased the pO(2), whereas doxorubicin did not cause any significant changes. Tumor physiology could potentially be used to optimize the sequence of neoadjuvant CT in breast cancer.

Cited by 181 publications

References 24 publications

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation

Treatment with Imatinib in NSCLC is associated with decrease of phosphorylated PDGFR-β and VEGF expression, decrease in interstitial fluid pressure and improvement of oxygenation

An Intracellular Signal Pathway That Regulates Cancer Cell Adhesion in Response to Extracellular Forces

Patupilone Induced Vascular Disruption in Orthotopic Rodent Tumor Models Detected by Magnetic Resonance Imaging and Interstitial Fluid Pressure

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