Influence of an anti‐angiogenic treatment on 9L gliosarcoma: Oxygenation and response to cytotoxic therapy

Teicher, Beverly A.; Holden, Sylvia A.; Ara, Gulshan; Dupuis, Norman P.; Liu, Fang; Yuan, Jia; Inamori, Masahiko; Kakeji, Yoshihiro

doi:10.1002/ijc.2910610523

Cited by 107 publications

(55 citation statements)

References 21 publications

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“…Although VEGF increases vascular permeability, our data do not suggest that blocking VEGF decreases permeability to CPT-11, as delivery was improved rather than diminished. Vascular permeability is probably more important for large molecules (Teicher et al, 1995b), and less so for small molecules (Wildiers et al, 2002) such as CPT-11 and SN-38, which have molecular weights of 586 and 392 g mol À1 , respectively. In short, changes in vessel permeability do not seem to play a major role in the observed increased uptake of CPT-11.…”

Section: Anti-vegf Mab Does Not Impair Intratumoral Cpt-11 Deliverymentioning

confidence: 99%

“…However, counterintuitive results have seemingly been demonstrated in several settings. Hypoxia is unchanged or reduced with squalamine (Teicher et al, 1998), the combination of TNP-470 and minocycline (Teicher et al, 1995b), and with the anti-VEGF mAb A4.6.1 (Lee et al, 2000). In addition, interstitial fluid pressure (IFP) is significantly reduced by the latter agent in the LS174T colon carcinoma model (Lee et al, 2000).…”

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confidence: 99%

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Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Wildiers¹,

Guetens²,

Boeck³

et al. 2003

Br J Cancer

303

150

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Promising preclinical activity with agents blocking the function of vascular endothelial growth factor (VEGF) has been observed in various cancer types, especially with combination therapy. However, these drugs decrease microvessel density, and it is not known whether this reduced vessel density (VD) results in decreased delivery of concomitantly administered classical anticancer drugs. We designed an in vivo study to investigate the relation between VEGF-blocking therapy, tumoral blood vessels, and intratumoral uptake of anticancer drugs. Nude NMRI mice bearing colon adenocarcinoma (HT29) were treated with the anti-VEGFmAb A4.6.1 or placebo. After 1 week, CPT-11 was administered 1 h prior to killing the animals. In A4.6.1 treated tumours, there was a significant decrease in VD, more pronounced with potentially functional large vessels than endothelial cords. Interestingly, a trend to increased intratumoral CPT-11 concentration was observed (P ¼ 0.09). In parallel, we measured an increase in tumour perfusion, as estimated by high-performance liquid chromatography determination of intratumoural Hoechst 33342 concentration. In the growth delay study, CPT-11 was at least equally effective with or without pretreatment with A4.6.1. These data suggest that tumour vascular function and tumour uptake of anticancer drugs improve with VEGF-blocking therapy, and indicate the relevance for further investigations.

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Section: Anti-vegf Mab Does Not Impair Intratumoral Cpt-11 Deliverymentioning

confidence: 99%

mentioning

confidence: 99%

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Wildiers¹,

Guetens²,

Boeck³

et al. 2003

Br J Cancer

303

150

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“…Mechanistically, the potential anti-neoplastic properties of LMWH include anti-angiogenisis [2,3], effects on cellular matrix [4,5], and reduced cell proliferation [6]. In this regard, it is of interest to note that based on preclinical studies, anti-angiogensis agents can putatively serve as radio-sensitizers [7,8]. As Glioblastoma multiforme (GBM) is among the most vascular of all neoplasms,(and abundantly express vascular endothelial growth factor and platelet derived growth factor [9]) the use of LMWH as a therapeutic adjunct to radiotherapy was viewed as worthy of clinical testing.…”

Section: Introductionmentioning

confidence: 99%

Effect of dalteparin and radiation on survival and thromboembolic events in glioblastoma multiforme: a phase II ECOG trial

Robins

O’Neill

Gilbert

et al. 2007

Cancer Chemother Pharmacol

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Laboratory and clinical studies support the concept that heparins, particularly the low molecular component, may serve as an inhibitor of angiogenesis, providing anti-neoplastic effects. Further, treatment with low molecular weight heparin (LMWH) may provide prophylaxis for thromboembolic events (TEE), in glioblastoma (GBM) patients. Dalteparin (5000 u sub Q daily) was given with and after conventional radiotherapy to newly diagnosed GBM patients. Forty-five patients were accrued between 5/02 and 9/04; 3 were ineligible. At time of progression, patients could continue dalteparin in addition to standard regimens. Pretreatment characteristics included: Median age 61 (range 26-78); ECOG Performance status: 0=38%, 1=57%, 2=5%; gross total resection 45%. There were no grade 3/4 bleeding or thrombocytopenic events, and no TEE occurred while on dalteparin. Median time on dalteparin was 6.3 months, median time to progression was 3.9 months; median survival was 11.9 months. There was no significant improvement in survival when compared to the RTOG GBM database (with various radiation/drug doublets including BCNU) using recursive partitioning analysis. Historically the incidence of TEE in GBM patients is ∼30%. As this study suggests dalteparin reduces the incidence of TEE, and does not have significant overlapping toxicities with most other drugs, its testing in a combined modality approach with other medications may be warranted in future trials.

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“…Inhibitors of angiogenesis suppress microvessel outgrowth and reduce the tumor vascular density, which might lead to a further increase of hypoxia in the remaining tumor (2, 3). On the other hand, antiangiogenic agents were reported to also increase tumor blood flow and oxygen delivery, and a recent model, termed normalization of tumor vasculature, describes the destruction of immature vessels, concomitant recruitment of pericytes, and stabilization of intact vessels in response to antiangiogenic therapy (4,5). This transient normalization window with increased blood flow and tumor oxygenation provides a rationale for concomitantly applied radiotherapy and chemotherapy (6).…”

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confidence: 99%

Ionizing Radiation Antagonizes Tumor Hypoxia Induced by Antiangiogenic Treatment

Riesterer

Honer

Jochum

et al. 2006

Clinical Cancer Research

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Purpose: The combined treatment modality of ionizing radiation with inhibitors of angiogenesis is effective despite the supposition that inhibition of angiogenesis might increase tumor hypoxia and thereby negatively affect radiation sensitivity. To directly assess this still controversial issue, we analyzed treatment-dependent alterations of tumor oxygenation in response to inhibition of angiogenesis alone, ionizing radiation, and combined treatment. Experimental Design: Serial measurements with high-resolution [18 F]fluoromisonidazole positron emission tomography and immunohistochemical detection of the endogenous hypoxia marker glucose transporter-1 were done to determine tumor hypoxia in a murine mammary carcinoma allograft model. Results: Inhibition of angiogenesis with the clinically relevant vascular endothelial growth factor receptor tyrosine kinase inhibitor PTK787/ZK222584 reduced microvessel density but had only minimal effects on tumor growth, tumor cell apoptosis, and proliferation. However, PTK787/ ZK222584 treatment increased overall and local tumor hypoxia as revealed by extended expression of the hypoxia marker glucose transporter-1and increased uptake of [ 18 F]fluoromisonidazole. Fractionated irradiation induced a strong growth delay, which was associated with enhanced apoptosis and reduced proliferation of tumor cells but only minor effects on microvessel density and allograft oxygenation. Combined treatment with fractionated irradiation resulted in extended tumor growth delay and tumor cell apoptosis but no increase in tumor hypoxia. Conclusions:These results show that irradiation antagonizes the increase of hypoxia by vascular endothelial growth factor receptor tyrosine kinase inhibition and abrogates the potential negative effect on tumor hypoxia.Thus, the risk of treatment-induced hypoxia by inhibitors of angiogenesis exists but is kept minimal when combined with a cytotoxic treatment modality.Hypoxia reduces the radiosensitivity of tumor cells. Cells irradiated in normoxic conditions are twice to thrice more radiosensitive than cells irradiated under severe hypoxia. Thus, a putative reduction of oxygen delivery in result to inhibition of angiogenesis and destruction of the tumor vasculature could render the tumor more radioresistant and as such would be of major clinical concern (ref. 1 and references therein). Chronic and acute hypoxia result from diffusion-limited processes and intermittent blood flow due to an imbalance of rapid tumor growth, insufficient tumor angiogenesis, and supply of oxygen. This can not only directly reduce the efficacy of chemotherapy and radiotherapy but also cause the selection of more aggressive and even highly angiogenic tumor cell populations, which are also potentially resistant to inhibitors of angiogenesis (2).Various classes of angiogenesis inhibitors exist. They either directly target the microvascular endothelial cell and in particular its endothelial growth factors and corresponding receptors or indirectly block the tumor stress response to ...

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Influence of an anti‐angiogenic treatment on 9L gliosarcoma: Oxygenation and response to cytotoxic therapy

Cited by 107 publications

References 21 publications

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Effect of antivascular endothelial growth factor treatment on the intratumoral uptake of CPT-11

Effect of dalteparin and radiation on survival and thromboembolic events in glioblastoma multiforme: a phase II ECOG trial

Ionizing Radiation Antagonizes Tumor Hypoxia Induced by Antiangiogenic Treatment

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