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. Jul-Aug 2008;28(4B):2027-31.

Dual Targeting of Tumor Vasculature: Combining Avastin and Vascular Disrupting Agents (CA4P or OXi4503)

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Free PMC article

Dual Targeting of Tumor Vasculature: Combining Avastin and Vascular Disrupting Agents (CA4P or OXi4503)

Dietmar W Siemann et al. Anticancer Res. .
Free PMC article

Abstract

Background: This study evaluated the therapeutic efficacy of combining vascular disrupting agents with antiangiogenic agents.

Materials and methods: Human clear cell renal carcinoma (Caki-1) tumors were established in nude mice. Treatments consisted of Avastin (2 mg/kg) administered twice a week; CA4P (100 mg/kg) or OXi4503 (25 mg/kg) administered 3 times a week for a period of 2 weeks; or a combination of Avastin and CA4P or OXi4503. Tumor response was assessed by growth delay.

Results: The tumor growth delays were 8, 6, and 18 days for Avastin, CA4P, and OXi4503, respectively. When the two therapies were combined, there was a significantly greater tumor response than what was achieved with single-agent treatments. For example, Avastin plus CA4P led to a growth delay of 13 days, and 27 days for Avastin plus OXi4503.

Conclusion: Vascular-directed therapies that include both antiangiogenic and vascular disrupting therapeutics can result in significantly enhanced antitumor effects.

Figures

Figure 1
Figure 1
H&E sections of Caki-1 tumors from mice 24 hours after treatment with (A) 100 mg/kg CA4P or (B) 25 mg/kg OXi4503. Arrows indicate the viable rim of tumor tissue surviving VDA treatment.
Figure 2
Figure 2
Response of Caki-1 tumors to Avastin (2 mg/kg, twice a week for 2 weeks), CA4P or Oxi4503 (100 mg/kg or 25 mg/kg, respectively, 3 times a week for 2 weeks), or the combination of AI and VDA. Data shown represent median tumor responses of groups of 8 to 10 mice.
Figure 3
Figure 3
Tumor growth delay in Caki-1 tumors treated with Avastin and/or either CA4P or OXi4503, administered as described in Figure 2. Data shown are the median, 75th and 90th percentiles of responses of tumors treated at a starting size of 200 mm3. Results in mice treated with combination therapy were significantly greater than those obtained in mice treated only with a single therapy (p<0.05, Wilcoxon rank sum test).
Figure 4
Figure 4
Tumor growth delay of Caki-1 tumors treated with Avastin and/or OXi4503. The treatment schedule is described in Figure 2; however, the dose of OX14503 was 10 mg/kg. The data shown are the median, 75th and 90th percentiles of responses of tumors treated at a starting size of 200 mm3.
Figure 5
Figure 5
Response of Caki-1 tumors to Avastin (2 mg/kg, twice a week for 3 weeks), OXi4503 (10 mg/kg, 3 times a week for 3 weeks), and a combination of both. The data shown are the median, 75th and 90th percentiles of responses of tumors treated at a starting size of 200 mm3.

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