Combretastatin A-4 prodrug inhibits growth of human non–small cell lung cancer in a murine xenotransplant model Arnd S Boehle, MD, Bence Sipos, MD, Ursula.

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Combretastatin A-4 prodrug inhibits growth of human non–small cell lung cancer in a murine xenotransplant model Arnd S Boehle, MD, Bence Sipos, MD, Ursula Kliche, Holger Kalthoff, PhD, Peter Dohrmann, PhD The Annals of Thoracic Surgery Volume 71, Issue 5, Pages 1657-1665 (May 2001) DOI: 10.1016/S0003-4975(01)02408-0 Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 1 H3-Thymidine incorporation assay. (A) Three hours of exposure to 10−4 mol/L CA-4PD induced in KNS-62 a 37% inhibition of proliferation; in Colo-699 this concentration inhibited proliferation by 69% (∗∗ p < 0.01; bars, SD). (B) Prolongation of drug exposure to 24 hours augmented the antiproliferative effect of CA-4PD on human lung cancer cells; a 10−8 mol/L concentration was effective in reducing proliferation by 49% and 59%, respectively (∗∗ p < 0.01; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 2 Cell viability assay. (A) Three hours of exposure to 10−4 mol/L CA-4PD reduced cell viability in KNS-62 by 31% (∗∗ p < 0.01). In Colo-699, 10−5 mol/L CA-4PD reduced cell viability by 21% (∗ p < 0.05; bars, SD). (B) Prolongation of CA-4PD exposure increased the cytotoxic effect; 10−8 mol/L effected significant reductions in cell viability for both cell lines (∗ p < 0.05; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 3 Tumor volume after subcutaneous xenotransplantation of human adenocarcinoma (Colo-699) of the lung. After subcutaneous xenotransplantation of Colo-699 the average tumor volume measured 100 mm3 on day 23, when intraperitoneal application of 50 mg/kg CA-4PD for 21 days was started (arrow). Tumors in control animals continued exponential growth, whereas systemic application of CA-4PD delayed tumor growth significantly (∗∗ p < 0.01; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 4 Tumor volume after subcutaneous xenotransplantation of human squamous cell carcinoma (KNS-62) of the lung. After subcutaneous xenotransplantation of KNS-62 the average tumor volume measured 100 mm3 on day 17, when intraperitoneal application of 50 mg/kg CA-4PD for 21 days was started (arrow). Systemic application of CA-4PD induced a significant growth delay in subcutaneously induced human squamous cell carcinoma (∗ p < 0.05; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 5 Microvessel count did not differ significantly between treated tumors and untreated controls (MVD = microvessel density; n.s. = not significant). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 6 Systemic application of CA-4PD induced marked rise of VEGF and bFGF staining indices in comparison to untreated controls (n.s. = not significant; bFGF = basic fibroblast growth factor; VEGF = vascular endothelial growth factor; ∗ p < 0.05; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 7 Systemic treatment by CA-4PD markedly reduces the proportion of proliferating tumor cells (∗∗ p < 0.01; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 8 The fraction of apoptotic cells is not significantly altered by systemic CA-4PD application (n.s. = not significant; ∗ p < 0.05; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 9 Magnetic resonance image 21 days after orthotopic tumor induction. At the site of tumor induction in the upper left lung a prominent tumor developed, penetrating the thoracic wall and infiltrating the subcutaneous fat tissue, thereby lifting the left extremity. The lungs are surrounded by malignant pleural effusions in both pleural cavities subsequent to the growth of metastasis in the mediastinum and both pleural cavities. The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions

Fig 10 Experimental animal survival after intrapulmonary tumor induction. Systemic application of 50 mg/kg CA-4PD prolonged animal survival after xenotransplantation of a human adenocarcinoma of the lung (Colo-699) by 29%. After xenotransplantation of a human squamous cell carcinoma of the lung (KNS-62), survival was prolonged by 35%. (∗ p < 0.05; ∗∗ p < 0.01; bars, SD). The Annals of Thoracic Surgery 2001 71, 1657-1665DOI: (10.1016/S0003-4975(01)02408-0) Copyright © 2001 The Society of Thoracic Surgeons Terms and Conditions