Changes in tumor vascularization after irradiation, anthracyclin, or antiangiogenic treatment in nitrosomethyl ureas-induced rat mammary tumors.

PURPOSE Changes in tumor vascularization may be involved in tumor regression after anticancer treatments. We therefore studied the relationship between tumor vascularization and tumor response according to treatment by irradiation (RT), epirubicin (EPI), or antiangiogenic agent TNP-470 in a nitrosomethyl-ureas-induced rat mammary tumor model by measuring the changes in tumor blood flow using high-frequency Power-Doppler sonography. EXPERIMENTAL DESIGN Mammary tumors were induced in female Sprague-Dawley rats by a single s.c. injection of nitrosomethyl-ureas. After tumor areas reached 2 cm(2), the animals received four weekly injections of epirubicin (EPI group), or a single fraction of 18 Gy (RT group), or six injections of TNP-470 within 12 days (TNP group), or both (RT combined with TNP-470, RT+TNP group). Power-Doppler sonography quantification of tumor vascularization (PDI) was performed before and 12 days after initiation of treatment. Tumor shrinkage was later evaluated and compared with the early changes in PDI values. RESULTS Compared with the control group, EPI induced an arrest in tumor growth. A similar effect was obtained with TNP-470. There was a decrease in tumor area after RT, but administration of TNP-470 combined with RT did not further enhance this effect. Changes in tumor area paralleled changes in PDI in the EPI group. Furthermore, changes in PDI 7 days after RT were associated with further tumor change in the RT groups, whereas they were independent of the antitumor effect of TNP-470. CONCLUSIONS Changes in functional tumor vascularization evolution appeared to be closely associated with tumor regression after anticancer treatment.

[1]  S. Påhlman,et al.  The Angiogenesis Inhibitor TNP-470 Reduces the Growth Rate of Human Neuroblastoma in Nude Rats , 1997, Pediatric Research.

[2]  F. Khuri,et al.  Safety and pharmacokinetic effects of TNP-470, an angiogenesis inhibitor, combined with paclitaxel in patients with solid tumors: evidence for activity in non-small-cell lung cancer. , 2002, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[3]  K. Hirata,et al.  Inhibition of Liver Metastasis of Human Pancreatic Carcinoma by Angiogenesis Inhibitor TNP‐470 in Combination with Cisplatin , 1998, Japanese journal of cancer research : Gann.

[4]  M Hiraoka,et al.  An antiangiogenic agent (TNP-470) inhibited reoxygenation during fractionated radiotherapy of murine mammary carcinoma. , 1997, International journal of radiation oncology, biology, physics.

[5]  D R Pickens,et al.  Quantified color Doppler sonography of tumor vascularity in an animal model. , 1999, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[6]  E F Donnelly,et al.  Quantified power Doppler US of tumor blood flow correlates with microscopic quantification of tumor blood vessels. , 2001, Radiology.

[7]  François Tranquart,et al.  In vivo quantitation of tumour vascularisation assessed by Doppler sonography in rat mammary tumours. , 2002, Ultrasound in medicine & biology.

[8]  Y. Kido.  Vascular endothelial growth factor (VEGF) serum concentration changes during chemotherapy in patients with lung cancer. , 2001, The Kurume medical journal.

[9]  D. Hallahan,et al.  Inhibition of vascular endothelial growth factor receptor signaling leads to reversal of tumor resistance to radiotherapy. , 2001, Cancer research.

[10]  S M Evans,et al.  Doppler ultrasound imaging detects changes in tumor perfusion during antivascular therapy associated with vascular anatomic alterations. , 2001, Cancer research.

[11]  D. Pickens,et al.  Quantification of tumor vascularity and flow with amplitude color Doppler sonography in an experimental model: preliminary results. , 1996, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[12]  K. Sudo,et al.  Significant inhibition of endothelial cell growth in tumor vasculature by an angiogenesis inhibitor, TNP-470 (AGM-1470). , 1994, Anticancer research.

[13]  P. Kristjansen,et al.  Therapeutic synergy of TNP-470 and ionizing radiation: effects on tumor growth, vessel morphology, and angiogenesis in human glioblastoma multiforme xenografts. , 2000, Clinical cancer research : an official journal of the American Association for Cancer Research.

[14]  V. Castronovo,et al.  TNP-470 (AGM-1470): mechanisms of action and early clinical development. , 1996, European journal of cancer.

[15]  A. Harris,et al.  Squamous cell head and neck cancer: evidence of angiogenic regeneration during radiotherapy. , 2001, Anticancer research.

[16]  S. Kook,et al.  Evaluation of solid breast lesions with power Doppler sonography , 1999, Journal of clinical ultrasound : JCU.

[17]  G. Durand,et al.  Time-course study of adipose tissue fatty acid composition during mammary tumor growth in rats with controlled fat intake. , 1995, Nutrition and cancer.

[18]  T. Ohnishi,et al.  Anti-proliferative effects of TNP-470 on human malignant gliomain vivo: potent inhibition of tumor angiogenesis , 2005, Journal of Neuro-Oncology.

[19]  R. Weichselbaum,et al.  Blockage of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. , 1999, Cancer research.

[20]  R. Weichselbaum,et al.  Blockade of the Vascular Endothelial Growth Factor Stress Response Increases the Antitumor Effects of Ionizing Radiation , 1999 .

[21]  B. Teicher,et al.  Comparison of several antiangiogenic regimens alone and with cytotoxic therapies in the Lewis lung carcinoma , 1996, Cancer Chemotherapy and Pharmacology.

[22]  S. Todo,et al.  Combined treatment with TNP-470 and 5-fluorouracil effectively inhibits growth of murine colon cancer cells in vitro and liver metastasis in vivo. , 2000, Oncology reports.

[23]  P. Hahnfeldt,et al.  Clinical application of antiangiogenic therapy: microvessel density, what it does and doesn't tell us. , 2002, Journal of the National Cancer Institute.

[24]  E. Rofstad,et al.  Vascular changes in a human malignant melanoma xenograft following single-dose irradiation. , 1984, Radiation Research.

[25]  G. Martiny-Baron,et al.  Effects of PTK787/ZK 222584, a specific inhibitor of vascular endothelial growth factor receptor tyrosine kinases, on primary tumor, metastasis, vessel density, and blood flow in a murine renal cell carcinoma model. , 2000, Cancer research.

[26]  G. Denardo,et al.  Blood flow in irradiated mouse sarcoma as determined by the clearance of xenon-133. , 1972, Cancer research.

[27]  Y. Shibamoto,et al.  Variations of the hypoxic fraction in the SCC VII tumors after single dose and during fractionated radiation therapy: assessment without anesthesia or physical restraint of mice. , 1991, International journal of radiation oncology, biology, physics.