RECENT PUBLICATIONS

ZD6126:

Bradley, D. P., Tessier, J. J., Ashton, S. E., Waterton, J. C., Wilson, Z., Worthington, P. L., and Ryan, A. J. (2007) Correlation of MRI biomarkers with tumor necrosis in Hras5 tumor xenograft in athymic rats. Neoplasia 9, 382-391. (read abstract)

Hinnen, P., and Eskens, F. A. (2007) Vascular disrupting agents in clinical development. Br J Cancer 96, 1159-1165. (read abstract)

Lenz, E. M., D'Souza, R. A., Jordan, A. C., King, C. D., Smith, S. M., Phillips, P. J., McCormick, A. D., and Roberts, D. W. (2007) HPLC-NMR with severe column overloading: fast-track metabolite identification in urine and bile samples from rat and dog treated with [14C]-ZD6126. J Pharm Biomed Anal 43, 1065-1077. (read abstract)

Gamrekelashvili, J., Kruger, C., von Wasielewski, R., Hoffmann, M., Huster, K. M., Busch, D. H., Manns, M. P., Korangy, F., and Greten, T. F. (2007) Necrotic tumor cell death in vivo impairs tumor-specific immune responses. J Immunol 178, 1573-1580. (read abstract)

Lippert, J. W. r. (2007) Vascular disrupting agents. Bioorg Med Chem 15, 605-615. (read abstract)

Masunaga, S., Nagasawa, H., Nagata, K., Suzuki, M., Uto, Y., Hori, H., Kinashi, Y., and Ono, K. (2007) Dependency of the effect of a vascular disrupting agent on sensitivity to tirapazamine and gamma-ray irradiation upon the timing of its administration and tumor size, with reference to the effect on intratumor quiescent cells. J Cancer Res Clin Oncol 133, 47-55. (read abstract)

Bozec, A., Lassalle, S., Gugenheim, J., Fischel, J. L., Formento, P., Hofman, P., and Milano, G. (2006) Enhanced tumour antiangiogenic effects when combining gefitinib with the antivascular agent ZD6126. Br J Cancer 95, 722-728. (read abstract)

Shaked, Y., Bertolini, F., Emmenegger, U., Lee, C. R., and Kerbel, R. S. (2006) On the origin and nature of elevated levels of circulating endothelial cells after treatment with a vascular disrupting agent. J Clin Oncol 24, 4040. (read abstract)

Madhu, B., Waterton, J. C., Griffiths, J. R., Ryan, A. J., and Robinson, S. P. (2006) The response of RIF-1 fibrosarcomas to the vascular-disrupting agent ZD6126 assessed by in vivo and ex vivo 1H magnetic resonance spectroscopy. Neoplasia 8, 560-567. (read abstract)

Hoang, T., Huang, S., Armstrong, E., Eickhoff, J. C., and Harari, P. M. (2006) Augmentation of radiation response with the vascular targeting agent ZD6126. Int J Radiat Oncol Biol Phys 64, 1458-1465. (read abstract)

Beerepoot, L. V., Radema, S. A., Witteveen, E. O., Thomas, T., Wheeler, C., Kempin, S., and Voest, E. E. (2006) Phase I clinical evaluation of weekly administration of the novel vascular-targeting agent, ZD6126, in patients with solid tumors. J Clin Oncol 24, 1491-1498. (read abstract)

van Heeckeren, W. J., Bhakta, S., Ortiz, J., Duerk, J., Cooney, M. M., Dowlati, A., McCrae, K., and Remick, S. C. (2006) Promise of new vascular-disrupting agents balanced with cardiac toxicity: is it time for oncologists to get to know their cardiologists? J Clin Oncol 24, 1485-1488. (read abstract)

Cullis, E. R., Kalber, T. L., Ashton, S. E., Cartwright, J. E., Griffiths, J. R., Ryan, A. J., and Robinson, S. P. (2006) Tumour overexpression of inducible nitric oxide synthase (iNOS) increases angiogenesis and may modulate the anti-tumour effects of the vascular disrupting agent ZD6126. Microvasc Res 71, 76-84. (read abstract)

Skliarenko, J. V., Lunt, S. J., Gordon, M. L., Vitkin, A., Milosevic, M., and Hill, R. P. (2006) Effects of the vascular disrupting agent ZD6126 on interstitial fluid pressure and cell survival in tumors. Cancer Res 66, 2074-2080. (read abstract)

Breidahl, T., Nielsen, F. U., Stodkilde-Jorgensen, H., Maxwell, R. J., and Horsman, M. R. (2006) The effects of the vascular disrupting agents combretastatin A-4 disodium phosphate, 5,6-dimethylxanthenone-4-acetic acid and ZD6126 in a murine tumour: a comparative assessment using MRI and MRS. Acta Oncol 45, 306-316. (read abstract)

O'Reilly, M. S. (2006) Radiation combined with antiangiogenic and antivascular agents. Semin Radiat Oncol 16, 45-50. (read abstract)

Raben, D., and Ryan, A. (2005) Vascular-targeting agents and radiation therapy in lung cancer: where do we stand in 2005? Clin Lung Cancer 7, 175-179. (read abstract)

Shi, W., and Siemann, D. W. (2005) Targeting the tumor vasculature: enhancing antitumor efficacy through combination treatment with ZD6126 and ZD6474. In Vivo 19, 1045-1050. (read abstract)

Kleespies, A., Kohl, G., Friedrich, M., Ryan, A. J., Barge, A., Jauch, K. W., and Bruns, C. J. (2005) Vascular targeting in pancreatic cancer: the novel tubulin-binding agent ZD6126 reveals antitumor activity in primary and metastatic tumor models. Neoplasia 7, 957-966. (read abstract)

Masunaga, S., Nagasawa, H., Uto, Y., Hori, H., Ohnishi, K., Takahashi, A., Ohnishi, T., Suzuki, M., Nagata, K., Kinashi, Y., and Ono, K. (2005) Combination of the antivascular agent ZD6126 with hypoxic cytotoxin treatment, with reference to the effect on quiescent tumor cells and the dependency on p53 status of tumor cells. Oncol Rep 14, 393-400. (read abstract)

Taraboletti G, Micheletti G, Dossi R, Borsotti P, Martinelli M, Fiordaliso F, Ryan AJ, Giavazzi R. Potential antagonism of tubulin-binding anticancer agents in combination therapies. Clin Cancer Res. 11(7): 2720-6, 2005. (read abstract)

Wachsberger PR, Burd R, Marero N, Daskalakis C, Ryan A, McCue P, Dicker AP. Effect of the tumor vascular-damaging agent, ZD6126, on the radioresponse of U87 glioblastoma. Clin Cancer Res. 11(2 Pt 1): 835-42, 2005. (read abstract)

Goto H, Yano S, Matsumori Y, Ogawa H, Blakey DC, Sone S. Sensitization of tumor-associated endothelial cell apoptosis by the novel vascular-targeting agent ZD6126 in combination with cisplatin. Clin Cancer Res. 10(22): 7671-6, 2004. (read abstract)

Siemann DW, Shi W. Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors. Int J Radiat Oncol Biol Phys. 60(4): 1233-40, 2004. (read abstract)

RECENT ANGIOGENE PRESS RELEASES:

Medicinova announce completion of initial Phase I clinical study of MN-029 OXFORD-July 6th., 2006

On June 4th., 2006 at the American Society of Clinical Oncology (ASCO) meeting in Atlanta, Georgia, our partners MediciNova Inc. presented results from the first Phase I clinical trial of the Vascular Disrupting Agent (VDA) MN-029, licensed from Angiogene Pharmaceuticals Ltd. in 2002. In this open-label, dose-escalation, safety and pharmacokinetic study, MN-029 was administered as an intravenous infusion once every 3 weeks with a 20 day recovery period between doses to patients with a broad range of solid tumours for whom no standard therapy was available. The results presented at ASCO by Dr. Alejandro Ricart of the Institute for Drug Development, Cancer Therapy and Research Center in San Antonio, Texas (Poster Number: AA12, Abstract No: 3096) established a maximum tolerated dose (MTD) for MN-029 of 180 mg/m2. As with other VDAs the most common side effects observed included nausea, vomiting, fatigue and diarrhea. Nine of 34 patients had stable disease after 3 cycles of treatment, including 2 patients with carcinoid tumors who received 26 cycles and 23 cycles, respectively.  Importantly, tumour blood flow, which is considered a potential predictor of clinical efficacy, was shown by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) to be reduced at well-tolerated doses below MTD. Commenting on these encouraging results, Yuichi Iwaki, M.D., Ph.D., Executive Chairman and CEO of MediciNova, Inc. stated that  “Demonstration of pharmacologic proof-of-concept and completion of the Phase I clinical program for MN-029 is an important milestone for MediciNova. Based upon these findings, we plan to initiate Phase II/III studies in more than one type of solid tumor cancer later this year.” Additional details can found in the associated Press Release on the MediciNova website.

Angiogene Reacquires Rights to ZD6126 (ANG453) from AstraZeneca OXFORD-March 7th., 2006

Angiogene announces that AstraZeneca has returned all rights to the Vascular Targeting Agent ZD6126 (previously ANG453). This novel agent for the therapy of solid tumours has been shown to markedly reduce tumour blood flow in Phase I studies and had advanced to Phase II. The clinical programme has been on hold pending the results of laboratory studies aimed at understanding and identifying management strategies for the side effect profile of ZD6126. These investigations have been successful.

AstraZeneca has subsequently made the decision to concentrate on other aspects of their pipeline and Angiogene is now seeking another partner for the development of this innovative experimental drug.

Peter Davis, Chief Executive Officer of Angiogene Pharmaceuticals said: "Although the clinical development of ZD6126 has had some difficulties, preclinical investigations carried out by AstraZeneca scientists have indicated a clear path forward for this programme. Tumour vasculature has been recently validated as a target by the approval of the antiangiogenic antibody bevacizumab. I am hopeful that the reduction in tumour blood flow, which will starve the tumour of essential oxygen and nutrients, will translate into clear patient benefit. We thank AstraZeneca for their efforts which have provided proof-of-principle for this strategy and now look forward to restarting this exciting project."

MediciNova announce initiation of a 2nd Phase I trial of MN-029 OXFORD-June 17th., 2005

MediciNova Inc. announced today the initiation of a second Phase I trial of the vascular disrupting agent MN-029, licenced from Angiogene in 2002. According to Dr. Richard E. Gammons the Chief Development Officer at MediciNova, “MN-029 has been well tolerated at each dosing level throughout the current Phase I clinical study, and we are planning in this second study to implement a more aggressive, yet simpler dosing schedule that will be compatible with a wide range of cancer treatment regimens". Further details can be found in the Press Release on the MediciNova website.

COMMENTARY ARCHIVE

Evaluating the therapeutic efficacy of vascular disrupting agents in early clinical studies OXFORD-July 3rd., 2007

The magnitude of the tumour cell death response produced by treatment with ZD6126 and other vascular disrupting agents (VDA) is critically dependent upon both the degree and duration of the blood flow shutdown that results. Although dynamic contrast enhanced magnetic resonance imaging (DCE-MRI) analysis carried out in the course of Phase I studies revealed dramatic reductions in tumour perfusion at well tolerated doses of ZD6126, the precise relationship between particular DCE-MRI parameters and subsequent tumour necrosis was not clearly established. In a paper published in May 2007 in the journal Neoplasia, Bradley et al., addressed this important question using a well characterized rat xenograft model. Importantly, this study employed doses of ZD6126 that produce plasma levels of the biologically active ZD6126 phenol derivative equivalent to those seen in Phase I studies. The results obtained provide convincing evidence of a correlation between the proportion of hypoperfused voxels measured 24 hours post-ZD6126 treatment and the extent of the resultant necrotic response. These data help justify the use DCE-MRI as a non-invasive means of assessing the potential efficacy of VDA treatment in future clinical studies. In particular, the measurement of equivalent enhancing fraction (EHF) and the presence of hypoperfused voxels as estimated from fit failures in Ktrans are likely to prove especially informative.

REFERENCE:

Bradley, D.P., Tessier, J.J., Ashton, S.E., Waterton, J.C., Wilson, Z., Worthington, P.L. and Ryan, A.J. (2007) Correlation of MRI biomarkers with tumor necrosis in Hras5 tumor xenograft in athymic rats. Neoplasia 9(5): 382-391. (read abstract)

All images and text © Angiogene Pharmaceuticals Ltd. Last updated July 15th., 2007