Vascular-targeted Drug Research Articles

Retinoblastoma Tumor Vessel Maturation Impacts Efficacy of Vessel Targeting in the LHBETATAGMouse Model

The aim of this study was to quantify tumor cell proliferation and growth, analyze tumor blood vessel development, and determine the efficacy of antiangiogenic and angiostatic therapy in targeting mature vessels in retinal tumors of the LH(BETA)T(AG) mouse model for retinoblastoma. LH(BETA)T(AG) mouse retinas were analyzed at 4, 8, 12, and 16 weeks of age. Tumor burden was analyzed by histology; cell proliferation, vessel density, angiogenesis, and vessel maturation were detected by immunofluorescence. To assess the efficacy of mature vessel targeting, 16-week-old mice were treated with single subconjunctival injections of the selective vascular-targeting drug combretastatin A4 prodrug (CA4P) or anecortave acetate, and eyes were analyzed 1 day and 1 week after injection to determine microvessel density and the number of angiogenic and mature vessels. Increased cell proliferation and angiogenesis were detected in the retinal inner nuclear layer (INL) before morphologic neoplastic changes were evident. As tumor size increased, angiogenesis diminished concomitantly with the appearance of mature vessels. Treatment with CA4P and anecortave acetate resulted in significant reductions in total vessel density. However, neither drug reduced the amount of alpha-smooth muscle actin (SMA)-positive, mature vessels. Results of this study provide new insight into the relationship between tumor growth and blood vessel development in the LH(BETA)T(AG) mouse and establish the framework for defining the selective action of two vessel-targeting drugs against new blood vessels compared with mature blood vessels. These findings suggest a high potential value in targeting the process of angiogenesis in the treatment of children with retinoblastoma.

Low-Dose Combretastatin A4 Phosphate Enhances the Immune Response of Tumor Hosts to Experimental Colon Carcinoma

Although there is a need to enhance the therapeutic efficiency in cancer by combining immunotherapeutic procedures with other therapy, combination with chemotherapy is complicated due to immunosuppressive effects of most chemotherapeutic drugs. The purpose of this investigation was to study whether combining tumor cell immunization with the vascular targeting drug combretastatin A4 phosphate (CA4P) would enhance tumor retardation and/or affect the antitumor immune response. Rats with intrahepatic colon carcinoma were immunized weekly with IL-18/IFNgamma-transfected tumor cells, starting day 9, and were treated with a low-dose CA4P (2 mg/kg, 5 days a week starting day 7). The effect of CA4P was studied on tumor growth and on immune reactivity in vitro. Rats with preexisting tumor, immunized and treated with low-dose CA4P, had a significantly retarded tumor growth compared with rats receiving CA4P or immunization alone. Splenocytes from rats treated with this combination had a significantly enhanced antitumor immune response compared with splenocytes from control rats. Exposure of nonadherent splenocytes to CA4P in vitro did not enhance their proliferation. However, 3-hour pretreatment of adherent splenocytes with 0.3 microg/mL CA4P significantly enhanced proliferation and IFNgamma production of admixed nonadherent splenocytes, partly due to nitric oxide reduction. Combining the nitric oxide synthase inhibitor N-nitro-l-arginine methyl ester with CA4P and immunization further retarded tumor growth. Concomitant treatment of rats with progressively growing tumor with immunization and low-dose CA4P significantly enhances the therapeutic effect as compared with either treatment alone and results in an enhanced antitumor immune reactivity.

Endocytosis pathways in endothelium: how many?

vascular endothelium is a cellular monolayer with the organization of a simple squamous epithelium that lines the entire cardiovascular system and constitutes a regulatable barrier between blood and tissues ([9][1], [17][2]). By its location, it is easily accessible to blood-borne drugs or imaging

MRI for assessing antivascular cancer treatments.

Selective antiangiogenesis and vascular targeting drugs hold out the promise of improved efficacy and tolerability for anticancer treatments. Early phase 1 drug trials have shown good tolerability for antiangiogenesis agents with biological activity below the maximum tolerated dose. Advanced clinical trials have demonstrated that morphological assessments of tumour response are of limited value in gauging the efficacy of treatment. MRI is a versatile technique which is sensitive to contrast mechanisms that can be affected by antivascular treatments; this use for MRI has been validated in xenografts and humans. Dynamic contrast-enhanced MRI (DCE-MRI), which demonstrates tissue perfusion and permeability, is being used clinically as a pharmacodynamic indicator of biological activity for antivascular cancer drugs. Early data show that DCE-MRI studies can define the biologically active dose and predict the efficacy of treatment on the basis of changes observed. MRI with macromolecular contrast media (MMCM) depicts microvessel permeability and fractional plasma volume. Xenograft studies with MMCM have shown great promise for evaluating antivascular treatments but this has not been used clinically. Intrinsic susceptibility-weighted MRI, which is sensitive to blood oxygenation and flow, is emerging as a technique that may be able to monitor vascular targeting therapies.

Semi-automated software for the three-dimensional delineation of complex vascular networks.

The understanding of tumour angiogenesis is of great importance in cancer research, as is the tumour response to vascular-targeted drugs. This paper presents software aimed at aiding these investigations and other situations where linear or dendritic structures are to be delineated from three-dimensional (3D) data sets. This software application was written to analyse the data from 3D data sets by allowing the manual and semi-automated tracking and delineation of the vascular tree, including the measurement of vessel diameter. A new algorithm, CHARM, based on a compact Hough transform and the formation of a radial map, has been used to locate vessel centres and measure diameters automatically. The robustness of this algorithm to image smoothing and noise has been investigated.

Combretastatin A-4 disodium phosphate: a vascular targeting agent that improves that improves the anti-tumor effects of hyperthermia, radiation, and mild thermoradiotheraphy

Purpose: To investigate the effect of combining the vascular targeting drug combretastatin A-4 disodium phosphate (CA4DP) with hyperthermia, radiation, or mild thermoradiotherapy in a transplanted C3H mouse mammary carcinoma.Methods and Materials: The C3H mammary carcinoma was grown on the rear foot of female CDF1 mice and treated when at 200 mm3 in size. CA4DP was dissolved in saline and injected i.p. Hyperthermia and/or radiation were locally given to tumors in restrained nonanesthetized mice. Tumor response was assessed using either a tumor growth or a tumor control assay. Mouse foot skin was used to assess normal tissue damage.Results: CA4DP significantly enhanced thermal damage in this tumor model. This effect was independent of drug doses between 25–400 mg/kg, but was strongly dependent on the time interval between drug injection and heating, with the greatest improvement seen when CA4DP preceded the heating by 1 h or less. There was also a suggestion of a temperature dependency with a 1.9-fold increase in heat damage at 42.5°C and a 2.6-fold increase at 41.5 and 40.5°C. Heat-induced normal tissue damage was also enhanced by combining CA4DP with heat, but the degree of enhancement was less than that seen in tumors. CA4DP (25 mg/kg) significantly increased radiation-induced local tumor control and this was further enhanced by combining CA4DP with mild temperature (41.5°C, 60 min) heating.Conclusions: CA4DP improved the anti-tumor effect of hyperthermia, especially at mild temperatures. More importantly, it also increased the tumor response to mild hyperthermia and radiation, which suggests that CA4DP may ultimately have an important application in clinical thermoradiotherapy.

77 The importance of sequence and timing on tumour response to combination treatment with radiation and vascular targeting drugs

77 The importance of sequence and timing on tumour response to combination treatment with radiation and vascular targeting drugs

Combretastatin A-4 and hyperthermia;a potent combination for the treatment of solid tumors

Background and purpose: Attacking tumor vasculature is a promising approach for the treatment of solid tumors. The tubulin inhibitor combretastatin A-4 disodium phosphate (CA-4) is a new vascular targeting drug which displays a low toxicity profile. We wanted to investigate how CA-4 influences tumor perfusion in the BT 4An rat glioma and how the vascular targeting properties of CA-4 could be exploited to augment hyperthermic damage towards tumor vasculature. Material and methods: We used the 86RbCl extraction technique to assess how CA-4 influences tumor perfusion, and the tumor endothelium was examined for morphological changes induced by the drug. We combined CA-4 (50 mg/kg i.p.) with hyperthermia (44°C, 60 min) at different time intervals to evaluate how therapy should be designed to affect tumor growth, and we studied the tumors histologically to assess tissue viability. Results: We found that CA-4 induced a profound, but transient reduction in tumor perfusion 3–6 h postinjection. If hyperthermia was administered 3–6 h after injecting CA-4, massive hemorrhagic necrosis developed, and tumor response was significantly enhanced compared to simultaneous administration of the two treatment modalities ( P<0.005). CA-4 alone had no influence on tumor growth and failed to disrupt the vasculature of the BT 4An solid tumors. Interestingly though, a mild endothelial edema was observed in some tumor areas 3 h after injecting CA-4. Conclusions: We conclude that the combination of CA-4 and hyperthermia is a potent therapeutic option for BT 4An tumors, but the selection of adequate time intervals between CA-4 and hyperthermia are imperative to obtain tumor response.

Improving local tumor control by combining vascular targeting drugs, mild hyperthermia and radiation.

Improvement in local control in a foot-implanted (200 mm3) C3H mouse mammary carcinoma by combining vascular targeting drugs, mild hyperthermia and radiation was investigated. The vascular targeting drug was flavone acetic acid (FAA; 150 mg/kg) intraperitoneally injected either 3 h before local tumor water-bath heating or 1 h after local tumor irradiation. For untreated tumors, the average (+/- 1 S.E.) tumor growth time (TGT; time to reach 5 x treatment volume) was 7.1 days (+/- 0.4). This was increased to 9.2 days (+/- 0.7) by using FAA. Heating also increased TGT, the effect being temperature and time dependent, and this heat response was further increased by FAA. The radiation dose (+/- 95% confidence interval) to control 50% of tumors (TCD50) 90 days after irradiation was 52 Gy (50-55) for radiation alone. This was decreased to 42 Gy (39-45) by FAA, 47 Gy (45-50) by heating (41.5 degrees C; 60 min) 4 h after irradiation, and to 28 Gy (22-35) by combining FAA and heat. Thus, vascular targeting drugs can improve the efficacy of mild hyperthermia and radiation.

Comparative effects of combretastatin A-4 disodium phosphate and 5,6-dimethylxanthenone-4-acetic acid on blood perfusion in a murine tumour and normal tissues

Purpose : To compare the ability of combretastatin A-4 disodium phosphate (CA4DP) and 5,6-dimethylxanthenone-4-acetic acid (DMXAA) to change tissue blood perfusion. Materials and methods : The tissues were a C3H mouse mammary carcinoma and various murine normal tissues, with perfusion measured using the 86 RbCl extraction technique. Results : CA4DP (250 mg/kg; i.p.) reduced tumour perfusion to 34% of that seen in controls within 1 h of injection. It was maintained at this for at least 6 h, returning to control levels by 24h. This decrease was dose-dependent. DMXAA (25 mg/kg; i.p.) caused a 79% reduction in tumour perfusion 6 h after injection; no recovery was observed even after 24 h. DMXAA showed no changes at doses below 10 mg/kg. Both CA4DP and DMXAA increased perfusion in the gut, kidney, bladder and lung, while decreasing splenic perfusion. CA4DP tended to decrease perfusion in muscle, while DMXAA increased liver perfusion. These changes in normal tissue perfusion were generally less than those changes seen in tumours. No significant changes were seen in skin. Conclusions : CA4DP and DMXAA produced a selective and significant reduction in tumour perfusion, but the pattern of change was different. These results suggest how these vascular targeting drugs should be combined with more conventional therapies.

Improving Local Tumor Control by Combining Vascular Targeting Drugs, Mild Hyperthermia and Radiation

Improvement in local control in a foot-implanted (200 mm3

2021 Enhancing local tumour control by combining radiation therapy and the vascular targeting drug combretastatin A-4 disodium phosphate

2021 Enhancing local tumour control by combining radiation therapy and the vascular targeting drug combretastatin A-4 disodium phosphate