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Antiangiogenic Treatment Enhances Photodynamic Therapy Responsiveness in a Mouse Mammary Carcinoma¹

Clayton Center for Ocular Oncology, Childrens Hospital Los Angeles, Los Angeles, California 90027 [A. F., K. F. v. T., N. R., C. J. G.], and Departments of Pediatrics [C. J. G., M. A. S.], Radiation Oncology [C. J. G.], Medicine [P. S. G.], Pathology [P. S. G.], and Surgery [M. A. S.], Keck School of Medicine, University of Southern California, Los Angeles, California 90033

	ABSTRACT

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Photodynamic therapy (PDT) is a promising cancer treatment that induces localized tumor destruction via the photochemical generation of cytotoxic singlet oxygen. PDT-mediated oxidative stress elicits direct tumor cell damage as well as microvascular injury within exposed tumors. Reduction in vascular perfusion associated with PDT-mediated microvascular injury produces tumor tissue hypoxia. Using a transplantable BA mouse mammary carcinoma, we show that Photofrin-mediated PDT induced expression of the hypoxia-inducible factor-1 (HIF-1) subunit of the heterodimeric HIF-1 transcription factor and also increased protein levels of the HIF-1 target gene, vascular endothelial growth factor (VEGF), within treated tumors. HIF-1 and VEGF expression were also observed following tumor clamping, which was used as a positive control for inducing tissue hypoxia. PDT treatment of BA tumor cells grown in culture resulted in a small increase in VEGF expression above basal levels, indicating that PDT-mediated hypoxia and oxidative stress could both be involved in the overexpression of VEGF. Tumor-bearing mice treated with combined antiangiogenic therapy (IM862 or EMAP-II) and PDT had improved tumoricidal responses compared with individual treatments. We also demonstrated that PDT-induced VEGF expression in tumors decreased when either IM862 or EMAP-II was included in the PDT treatment protocol. Our results indicate that combination procedures using antiangiogenic treatments can improve the therapeutic effectiveness of PDT.

	Introduction

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PDT³ involves treating solid malignancies with tissue-penetrating laser light following the systemic administration of a tumor localizing photosensitizer (1) . Properties of photosensitizer localization in tumor tissue and photochemical generation of reactive oxygen species are combined with precise delivery of laser-generated light to produce a treatment offering local tumoricidal activity (2 , 3) . The porphyrin photosensitizer PH recently received Food and Drug Administration approval for PDT treatment of esophageal and endobronchial carcinomas (1) . PDT is also undergoing clinical evaluation for the treatment of bladder, head and neck, brain, intrathoracic, and skin malignancies (1) . PDT targets include tumor cells, tumor microvasculature, inflammatory cells, and immune host cells (1, 2, 3) . Vascular effects induced by PH-mediated PDT include perfusion changes, vessel constriction, macromolecular vessel leakage, leukocyte adhesion, and thrombus formation (1 , 4) . These effects appear to be linked to platelet activation and release of thromboxane (5) . Microvasculature damage is readily observed histologically following PDT and leads to a significant decrease in blood flow as well as severe and persistent tumor tissue hypoxia (6 , 7) . Rapid and substantial reductions in tissue oxygenation can also occur during illumination by direct utilization of oxygen during the photochemical generation of reactive oxygen species (7 , 8) .

Tissue hypoxia induces a plethora of molecular and physiological responses, including an adaptive response associated with gene activation (9) . A primary step in hypoxia-mediated gene activation is the formation of the HIF-1 transcription factor complex (9 , 10) . HIF-1 is a heterodimeric complex of two helix-loop-helix proteins, HIF-1ß (ARNT) and HIF-1 (11) . ARNT is constitutively expressed, whereas HIF-1 is rapidly degraded under normoxic conditions. Hypoxia induces the stabilization of the HIF-1 subunit, which in turn allows for the formation of the transcriptionally active protein complex (11 , 12) . A number of HIF-1-responsive genes have been identified, including VEGF, erythropoietin, and glucose transporter-1 (11) . VEGF, also called vascular permeability factor, is an endothelial cell-specific mitogen involved in the induction and maintenance of the neovasculature in solid tumors (11 , 13) . VEGF expression increases in tumor tissue under hypoxia as a result of both transcriptional activation and increased stabilization (11 , 14) .

In the current study, we examined whether PDT-induced microvascular damage and the resulting hypoxia could serve as activators of molecular events leading to the increased expression of VEGF within treated tumor tissue. We also determined whether antiangiogenic compounds, which counter the actions of VEGF, could improve PDT tumor responsiveness. Our results document that PH-mediated PDT induces expression of HIF-1 and the transcription factor’s target gene, VEGF, in a transplanted mouse mammary carcinoma. We also document enhanced tumoricidal activity when PDT is combined with antiangiogenic therapy.

	Materials and Methods

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Drugs and Reagents.
The photosensitizer Photofrin porfimer sodium was a gift from QLT PhotoTherapeutics, Inc. (Vancouver, British Columbia, Canada) and was dissolved in 5% dextrose in water to make a 2.5 mg/ml stock solution. Recombinant EMAP-II was prepared as described previously (15) . A working solution at 10 µg/ml was prepared in PBS containing 0.1% BSA. IM862 was obtained from Cytran Inc. (Kirkland, WA) and was dissolved in saline to make a 5 mg/ml working solution (16) . CoCl₂ was obtained from Sigma Chemical Co. (St. Louis, MO), and a 10 mM stock solution was prepared in water.

Cells and in Vivo Tumor Model.
BA mouse mammary carcinoma cells (originally obtained from the NIH tumor bank) were used in all in vitro and in vivo experiments (17) . Cells were grown as a monolayer in RPMI 1640 supplemented with 10% FCS and antibiotics. The plating efficiency for the BA cells was 40–60%. s.c. BA mammary carcinomas were generated by trocar injection of 1-mm³ pieces of tumor to the hind right flank of 8- to 12-week-old female C3H/HeJ mice (17) .

In Vitro and in Vivo Treatment Protocols.
In vitro photosensitization protocols involved seeding cells into plastic Petri dishes and incubating overnight in complete growth medium to allow for cell attachment. PDT treatments included incubating cells in the dark at 37°C for 16 h with PH (25 µg/ml) in medium containing 5% FCS. Cells were then incubated for an additional 30 min in growth medium containing 10% FCS, rinsed in medium without serum, and exposed to red light (570–650 nm) generated by a parallel series of red Mylar-filtered 30 W fluorescent bulbs and delivered at a dose rate of 0.35 mW/cm². In specified experiments, cells were incubated with CoCl₂ (100 µM) in growth medium containing 5% FCS for 16 h. Treated cells were then re-fed with complete growth medium and incubated in the dark at 37°C until collected for analysis of VEGF secretion into the culture media. In vivo PDT tumor treatments were performed as reported previously on tumors measuring 6–7 mm in diameter (17) . Briefly, PDT procedures included an i.v. injection of PH (5 mg/kg) followed 24 h later with non-thermal laser tumor irradiation using an argon-pumped dye laser emitting red light at 630 nm. A light dose rate of 75 mW/cm² and a total light dose of 200 J/cm² were used for all in vivo PDT treatments. After treatment, tumors were measured three times per week. Cures were defined as being disease free for at least 40 days after PDT (17) . Antiangiogenic treatment was performed using either EMAP-II or IM862. Each compound was administered as daily i.p. injections for 10 consecutive days starting 1 h prior to PDT light treatment. Individual IM862 doses were 25 mg/kg, and individual EMAP-II doses were 50 µg/kg. Tumor tissue hypoxia was induced in selected experiments by clamping lesions for 45 min.

Western Blot Analysis.
Tumors were collected at various times after treatment, homogenized with a Polytron in 1x reporter lysis buffer (Promega, Madison, WI), and evaluated for protein expression as described previously (18) . Briefly, protein samples (30 µg) were size-separated on 10% (for HIF-1) or 12.5% (for VEGF) discontinuous polyacrylamide gels and transferred overnight to nitrocellulose membranes. Filters were blocked for 1 h with 5% nonfat milk and then incubated for 2 h with either a mouse monoclonal anti-HIF-1 antibody (clone 54; Transduction Laboratories, Lexington, KY), a rabbit polyclonal anti-VEGF antibody (no. sc-507; Santa Cruz Biotechnology, Santa Cruz, CA), or a mouse monoclonal antiactin antibody (clone C-4; ICN, Aurora, OH). Filters were then incubated with either an antimouse or antirabbit peroxidase conjugate (Sigma), and the resulting complexes were visualized by enhanced chemiluminescence autoradiography (Amersham Life Science, Chicago, IL).

ELISA Assays.
A Quantikine M mouse VEGF ELISA kit (R&D Systems, Minneapolis, MN) was used to quantify VEGF levels in cell culture media as well as in tumor extracts from control and treated mice. Results were normalized to protein concentrations from tumor tissue or cell lysates.

Statistics.
Statistical analysis was performed using a two-tailed Student’s t test to analyze VEGF levels and the ² test for evaluation of tumor cure rates.

	Results and Discussion

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PDT continues to show promise in the treatment of a variety of malignant and nonmalignant disorders (1 , 19) . The use of PDT for advanced esophageal tumors offers prolonged tumor responses compared with standard Nd-YAG laser ablation treatments. Extended tumor responses are also observed in advanced non-small cell lung cancer patients treated with PDT compared with Nd-YAG laser ablation. Likewise, PDT applications continue to be encouraging for early stage lung cancer, brain cancers, head and neck cancers, and for nononcological disorders such as age-related macular degeneration (1 , 19) . Nevertheless, recurrences are observed after PDT, and methods to improve the therapeutic efficacy of this procedure are needed. Multiple physiological, biophysical, and/or pharmacological variables may account for recurrences after PDT (2 , 3) . Nonuniform distribution of photosensitizers within tumor tissue, inadequate light distribution, photosensitizer photobleaching, and treatment-induced oxygen deprivation may all contribute to suboptimal PDT responses. In the current study, we examined molecular events associated with PDT-induced hypoxia with an emphasis on determining whether PDT effectiveness could be enhanced with antiangiogenic therapy.

Several laboratories have shown that PDT produces microvascular damage within treated tumors and that PDT leads to tumor tissue hypoxia (4, 5, 6, 7, 8) . Hypoxia mediates adaptive gene expression through the HIF transcription factor (9) . An initial step in hypoxia-mediated gene activation is the formation of the HIF-1 heterodimeric transcription factor complex (10) . One subunit, HIF-1ß (ARNT), is constitutively expressed, whereas the second subunit, HIF-1, is rapidly degraded under normoxic conditions by the ubiquitin-proteasome system (9 , 10 , 12) . Because hypoxia induces increased expression and stabilization of the HIF-1 subunit as well as activates the HIF-1 transcription complex, it seemed likely that PDT-induced microvascular damage and resulting tumor tissue hypoxia could also stabilize HIF-1 and initiate HIF-1-mediated transcription. Fig. 1A uses Western analysis to show that PDT treatment of BA mammary carcinoma tumors growing in C3H mice induced expression of HIF-1. This response was rapid, being observed within the first 5 min after PDT. Tumor clamping was used as a positive control and resulted in comparable HIF-1 expression. The HIF-1 complex functions via binding to a hypoxia response element found in the promoter region of the VEGF gene as well as in the 3' flanking region of the erythropoietin gene (11) . Expression of VEGF in areas around histologically documented tumor necrosis originally led to suggestions that hypoxia is a major regulator of tumor angiogenesis (13 , 14) . VEGF is a dimeric glycoprotein with strong mitogenic activity restricted primarily to endothelial cells (14) . Fig. 1B documents VEGF expression after in vivo PDT. Western analysis was performed under reducing conditions on tumor lysates collected 24 h after PDT. PDT and tumor clamping both induced significant increases in VEGF expression within treated lesions. VEGF-induced angiogenesis plays an important role in tumor growth. Inhibition of VEGF activity with neutralizing antibodies inhibits the growth of primary and metastatic tumors, and attenuation of VEGF expression decreases tumor growth and vascularity (20) . Our results suggest that PDT may be functioning as a mediator of tumor angiogenesis and tumor recurrence by enhancing expression of VEGF within the treated tumor mass (14) .

View larger version (15K): [in this window] [in a new window]   Fig. 1. PDT treatment of BA mammary carcinoma tumors growing in C3H mice induced expression of the transcription factor subunit HIF-1 and VEGF. A, tumors were collected immediately after treatment and evaluated for HIF-1 expression by Western immunoblot analysis. HIF-1 was not detectable in control tumors measuring 6–7 mm in diameter. Both PDT (5 mg/kg PH; 200 J/cm2) and tumor clamping (45 min) induced HIF-1 expression. B, separate tumors were collected 24 h after PDT or clamping (45 min) and assayed for VEGF expression by Western immunoblot analysis. Expression of actin was used to monitor protein loading.

View larger version (57K): [in this window] [in a new window]   Fig. 2. VEGF levels in culture media from control BA mammary carcinoma cells and from cells exposed to light alone, CoCl2, PH alone, or PDT. Culture medium was collected 2, 6, or 24 h after treatment, and VEGF concentrations were determined by ELISA. Each group represents the mean (bars, SE) of five individual experiments. A statistically significant difference in VEGF levels was observed only between CoCl2 and control samples (P < 0.05).

View larger version (19K): [in this window] [in a new window]   Fig. 3. Antiangiogenic treatments enhance the tumoricidal action of PDT. C3H mice transplanted with BA mammary carcinomas received daily injections for 10 days of either IM-862 (25 mg/kg per dose; n = 9) or EMAP-II (50 µg/kg per dose; n = 9) commencing 1 h prior to a single PDT treatment (5 mg/kg PH; 200 J/cm2). Mice were monitored for tumor recurrences three times per week for 40 days. Control conditions included individual antiangiogenic treatments alone (n = 9) and PDT treatment alone (n = 18). There was a statistically significant difference in the percentage of cures between PDT alone versus PDT + EMAP-II or PDT + IM862 (P < 0.05).

View larger version (48K): [in this window] [in a new window]   Fig. 4. The antiangiogenic compounds IM862 and EMAP-II can decrease VEGF levels in PDT-treated tumors. Tumor-bearing mice received no treatment (Control), PDT alone, or PDT plus two injections of either EMAP-II or IM862 (1 h prior to PDT and 23 h after PDT). Tumor samples were collected 24 h after PDT and assayed for VEGF expression using a commercial ELISA assay kit. Each group represents the mean (bars, SE) of six individual tumor samples. There was a statistically significant difference in VEGF levels between PDT alone and PDT plus EMAP-II (P < 0.01).

	ACKNOWLEDGMENTS

 
We thank QLT PhotoTherapeutics, Inc. (Vancouver, British Columbia, Canada) for the generous gift of Photofrin, and Cytran Inc. (Kirkland, WA) for the generous gift of IM862.

	FOOTNOTES

 
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This investigation was performed in conjunction with the Clayton Foundation for Research and was supported in part by USPHS Grants CA-31230, HL-60061, and HL-03981 from the NIH; Office of Naval Research Grant N000014-91-J-4047 from the Department of Defense; United States Army Medical Research Grant BC981102 from the Department of Defense; the Neil Bogart Memorial Fund of the T. J. Martell Foundation for Leukemia, Cancer and AIDS Research; and the Las Madrinas Endowment for Experimental Therapeutics in Ophthalmology.

² To whom requests for reprints should be addressed, at Childrens Hospital Los Angeles, Mail Stop 67, 4650 Sunset Boulevard, Los Angeles, CA 90027. Phone: (323) 669-2335, Fax: (323) 669-0742; E-mail: cgomer{at}hsc.usc.edu

³ The abbreviations used are: PDT, photodynamic therapy; PH, Photofrin porfimer sodium; HIF-1, hypoxia-inducible transcription factor; ARNT, aryl hydrocarbon nuclear receptor-translocator; VEGF, vascular endothelial growth factor; EMAP-II, endothelial-monocyte activating polypeptide.

⁴ R. Masood and P. Gill, unpublished data.

Received 4/19/00. Accepted 6/14/00.

	REFERENCES

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