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[Cancer Research 60, 4066-4069, August 1, 2000]
© 2000 American Association for Cancer Research

Advances in Brief

Antiangiogenic Treatment Enhances Photodynamic Therapy Responsiveness in a Mouse Mammary Carcinoma1

Angela Ferrario, Karl F. von Tiehl, Natalie Rucker, Margaret A. Schwarz, Parkash S. Gill and Charles J. Gomer2

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
Top
 ABSTRACT
Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 
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{alpha} (HIF-1{alpha}) 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{alpha} 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
Top
 ABSTRACT
 Introduction
Materials and Methods
 Results and Discussion
 REFERENCES
 
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{alpha} (11) . ARNT is constitutively expressed, whereas HIF-1{alpha} is rapidly degraded under normoxic conditions. Hypoxia induces the stabilization of the HIF-1{alpha} 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{alpha} 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
Top
 ABSTRACT
 Introduction
 Materials and Methods
Results and Discussion
 REFERENCES
 
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{alpha}) 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{alpha} 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 {chi}2 test for evaluation of tumor cure rates.


   Results and Discussion
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
REFERENCES
 
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{alpha}, 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{alpha} 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{alpha} and initiate HIF-1-mediated transcription. Fig. 1ACitation uses Western analysis to show that PDT treatment of BA mammary carcinoma tumors growing in C3H mice induced expression of HIF-1{alpha}. 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{alpha} 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. 1BCitation 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) .



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  		Fig. 1. PDT treatment of BA mammary carcinoma tumors growing in C3H mice induced expression of the transcription factor subunit HIF-1{alpha} and VEGF. A, tumors were collected immediately after treatment and evaluated for HIF-1{alpha} expression by Western immunoblot analysis. HIF-1{alpha} 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{alpha} 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.

 
We next examined whether in vitro PDT of BA mammary carcinoma cells could also induce expression of VEGF. Fig. 2Citation shows VEGF levels collected from culture media at various time intervals for control and treatment conditions. Exposure to CoCl2 served as a statistically significant positive control because exposure to this divalent metal induces cellular VEGF expression (11) . A 210 J/m2 PDT dose resulted in a modestly increase in VEGF levels when measured 24 h after treatment. The PDT doses (210 and 420 J/m2) and CoCl2 treatment produced clonogenic survival levels ranging from 33% to 96%. The in vitro PDT conditions would be expected to involve singlet oxygen-mediated oxidative stress but not induced hypoxia. These results suggest that the increase in VEGF expression observed in tumors after in vivo PDT may be associated with treatment-induced hypoxia and to a lesser extent with treatment-induced oxidative stress. Exposure of various mouse and human tumor cells to ionizing radiation and exposure of rat endothelial cells to hydrogen peroxide can up-regulate VEGF expression (20 , 21) . Additional studies will be required to determine similarities and differences in VEGF induction for various types of oxidative stress.



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  		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).

 
A growing number of reports have indicated that antiangiogenic agents can enhance the tumoricidal effectiveness of chemotherapy and radiation treatments (20 , 22 , 23) . We next examined whether antiangiogenic treatments, using either EMAP-II or IM862, could enhance the tumoricidal action of PDT. EMAP-II is a single chain polypeptide that inhibits tumor growth and has antiangiogenic activity (15) . EMAP-II induces apoptosis in growing capillary endothelial cells in both a time- and dose-dependent manner. EMAP-II also prevents vessel ingrowth in experimental angiogenesis models and in primary tumors. Interestingly, EMAP-II does not induce toxicity in normal organs. IM862 is a dipeptide of L-glutamyl-L-tryptophan that was initially isolated from the thymus (16) . Preclinical studies have shown that the dipeptide inhibits angiogenesis in chorioallantoic membrane assays and inhibits VEGF production in monocytic lineage cells.4 IM862 also inhibits tumor growth in xenograft models but has no direct cytotoxic effect on tumor cells. IM862 mediates these effects by inhibiting production of VEGF and by activating natural killer cells. Intranasal administration of IM862 exhibits antitumor activity in patients with AIDS-associated Kaposi’s sarcoma (16) . IM862 also appears to be safe and well tolerated when delivered over prolonged time periods. A PDT procedure that produced a moderate cure rate alone was used to measure positive or negative changes in tumor response when a single PDT treatment was combined with daily injections of EMAP-II or IM862 for 10 days (17) . Fig. 3Citation shows that antiangiogenic treatment statistically enhanced (P < 0.05) the tumoricidal action of PDT as measured by tumor cures. Specifically, the 200 J/cm2 PDT dose alone produced a 39% cure rate, whereas PDT plus EMAP-II or IM862 produced tumor cures of 89 and 78%, respectively. The antiangiogenic treatments alone did not produce any tumor cures or tumor regression and only slightly modified tumor growth parameters.



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  		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).

 
Finally, we examined whether the antiangiogenic derivatives used in this study modulated PDT-induced VEGF levels in treated tumors. The in vivo PDT dose delivered to tumors (200 J/cm2) induced rapid and severe tissue necrosis. Therefore, tumor samples were only collected 24 h after PDT. This timeframe allowed for two antiangiogenic drug doses (1 h prior to light treatment and 1 h prior to sacrifice). Fig. 4Citation shows a decrease in VEGF levels, measured by ELISA, in tumors treated with PDT combined with EMAP-II or IM862 compared with tumors treated with PDT alone. These results were obtained after only two doses of either EMAP-II or IM862. Nevertheless, a statistically significant decrease (P < 0.01) in PDT-induced VEGF levels was observed when EMAP-II was included in the treatment protocol. It is likely the 10 daily doses of EMAP-II or IM862 used in the PDT tumor treatment experiments would further attenuate VEGF levels.



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  		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).

 
In summary, we demonstrate that antiangiogenic treatments can potentiate PDT responsiveness. This result may involve attenuating the angiogenic actions of VEGF, which was observed to increase in PDT-treated tumors. Optimization of antiangiogenic parameters as well as an examination of various methods to block angiogenesis are being performed at present. The minimal systemic toxicity associated with antiangiogenic therapy suggests that these procedures should be compatible with clinical PDT and may provide an efficient strategy for selectively enhancing PDT tumor responsiveness. It will also be of clinical interest to determine whether antiangiogenic treatments can enhance PDT procedures for age-related macular degeneration because this pathology is marked by neovascularization (19) .


   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. Back

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 Back

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. Back

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

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


   REFERENCES
Top
 ABSTRACT
 Introduction
 Materials and Methods
 Results and Discussion
 REFERENCES
 

  1. Dougherty T. J., Gomer C. J., Henderson B. W., Jori G., Kessel D., Korbelik M., Moan J., Peng Q. Photodynamic therapy. J. Natl. Cancer Inst., 90: 889-905, 1998.[Abstract/Free Full Text]
  2. Henderson B. W., Dougherty T. J. How does photodynamic therapy work?. Photochem. Photobiol., 55: 145-157, 1992.[Medline]
  3. Oleinick N. L., Evans H. E. The photobiology of photodynamic therapy: cellular targets and mechanisms. Radiat. Res., 150: S146-S156, 1998.
  4. Fingar V. H., Wieman T. J., Wiehle S. A., Cerrito P. B. The role of microvascular damage in photodynamic therapy: the effect of treatment on vessel constriction, permeability, and leukocyte adhesion. Cancer Res., 52: 4914-4921, 1992.[Abstract/Free Full Text]
  5. Fingar V. H., Wieman T. J., Haydon P. S. The effects of thrombocytopenia on vessel stasis and micromolecular leakage after photodynamic therapy using Photofrin. Photochem. Photobiol., 66: 513-517, 1997.[Medline]
  6. van Geel I. P. J., Oppelaar H., Rijken P. F. J. W., Bernsen H. J. J. A., Hagemeier N. E. M., van der Kogel A. L., Hodgkiss R. J., Stewart F. A. Vascular perfusion and hypoxic areas in RIF-1 tumours after photodynamic therapy. Br. J. Cancer, 73: 288-293, 1996.[Medline]
  7. Sitnik T. M., Hampton J. A., Henderson B. W. Reduction of tumor oxygenation during and after photodynamic therapy in-vivo: effects of fluence rate. Br. J. Cancer, 77: 1386-1394, 1998.[Medline]
  8. Foster T. H., Murant R. S., Byrant R. G., Knox R. S., Gibson S. L., Hilf R. Oxygen consumption and diffusion effects in photodynamic therapy. Radiat. Res., 126: 296-303, 1991.[Medline]
  9. Ratcliffe P. J., O’Rourke J. F., Maxwell P. H., Pugh C. W. Oxygen sensing, hypoxia-inducible factor-1 and the regulation of mammalian gene expression. J. Exp. Biol., 201: 1153-1162, 1998.[Abstract]
  10. Wang G. L., Semenza G. L. General involvement of hypoxia-inducible factor in transcriptional response to hypoxia. Proc. Natl. Acad. Sci. USA, 90: 4303-4308, 1993.
  11. Forsythe J. A., Jiang B-H., Iyer N. V., Agani F., Leung S. W., Koos R. D., Semenza G. L. Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol. Cell Biol., 16: 4604-4613, 1996.[Abstract]
  12. Huang L. E., Gu J., Schau M., Bunn H. F. Regulation of hypoxia-inducible factor 1a is mediated by an oxygen dependent degradation domain via the ubiquitin proteasome pathway. Proc. Natl. Acad. Sci. USA, 95: 7987-7992, 1998.[Abstract/Free Full Text]
  13. Senger D. R., Peruzzi C. A., Feder J., Dvorak H. F. A highly conserved vascular permeability factor secreted by a variety of human and rodent tumor cell lines. Cancer Res., 46: 5629-5632, 1986.[Abstract/Free Full Text]
  14. Shweiki D., Itin A., Soffer D., Keshet E. Vascular endothelial growth factor induced by hypoxia may mediate hypoxia-initiated angiogenesis. Nature (Lond.), 359: 843-845, 1992.[Medline]
  15. Schwarz, M. A., Kandel, J., Brett, J., Li, J., Hayward, J., Schwarz, R. E., Chappey, O., Wautier, J-L., Chabot, J., Gerfo, P. L, and Stern, D. Endothelial-monocyte activating polypeptide II, a novel antitumor cytokine that suppresses primary and metastatic tumor growth and induces apoptosis in growing endothelial cells. J. Exp. Med., 190: 341–353, 1999.
  16. Tulpule A., Scadden D. T., Espina B. M., Cabriales S., Howard W., Shea K., Gill P. S. Results of a randomized study of IM862 nasal solution in the treatment of AIDS-related Kaposi’s sarcoma. J. Clin. Oncol., 18: 716-723, 2000.[Abstract/Free Full Text]
  17. Ferrario A., Kessel D., Gomer C. J. Metabolic properties and photosensitizing responsiveness of mono-L-aspartyl chlorin e6 in a mouse tumor model. Cancer Res., 52: 2890-2893, 1992.[Abstract/Free Full Text]
  18. Fisher A. M. R., Ferrario A., Rucker N., Zhang S., Gomer C. J. Photodynamic therapy sensitivity is not altered in human tumor cells after abrogation of p53 function. Cancer Res., 59: 331-335, 1999.[Abstract/Free Full Text]
  19. Miller J. W., Schmidt-Erfurth U., Sickenberg M., Pournaras C. J., Laqua H., Barbazetto I., Zografos L., Piguet B., Donati G., Lane A. M., Birngruber R., van den Berg H., Strong A., Manjuris U., Gray T., Fsadni M., Bressler N. M., Gragoudas E. S. , Photodynamic therapy with verteporfin for choroidal neovascularization caused by age-related macular degeneration: results of a single treatment in a phase 1 and 2 study. Arch. Ophthalmol., 117: 1161-1173, 1999.[Abstract/Free Full Text]
  20. Gorski D. H., Beckett M. A., Jaskowiak N. T., Calvin D. P., Mauceri H. J., Salloum R. M., Seetharam S., Koons A., Hari D. M., Kufe D. W., Weichselbaum R. R. Blockade of the vascular endothelial growth factor stress response increases the antitumor effects of ionizing radiation. Cancer Res., 59: 3374-3378, 1999.[Abstract/Free Full Text]
  21. Chua C. C., Hamdy R. C., Chua B. H. Upregulation of vascular endothelial growth factor by H2O2 in rat heart endothelial cells. Free Radic. Biol. Med., 25: 891-897, 1998.[Medline]
  22. Teicher B. A., Sotomayor E. A., Huang Z. D. Antiangiogenic agents potentiate cytotoxic cancer therapies against primary and metastatic disease. Cancer Res., 52: 6702-6704, 1992.[Abstract/Free Full Text]
  23. Mauceri H. J., Hanna N. N., Beckett M. A., Gorski D. H., Staba M. J., Stellato K. A., Bigelow K., Heimann R., Gately S., Dhanabal M., Soff G. A., Sukhatme V. P., Kufe D. W., Weichselbaum R. R. Combined effects of angiostatin and ionizing radiation in antitumor therapy. Nature (Lond.), 394: 287-291, 1998.[Medline]



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A. Ferrario, C. F. Chantrain, K. von Tiehl, S. Buckley, N. Rucker, D. R. Shalinsky, H. Shimada, Y. A. DeClerck, and C. J. Gomer
The Matrix Metalloproteinase Inhibitor Prinomastat Enhances Photodynamic Therapy Responsiveness in a Mouse Tumor Model
Cancer Res., April 1, 2004; 64(7): 2328 - 2332.
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M. Makowski, T. Grzela, J. Niderla, M. Lazarczyk, P. Mroz, M. Kopee, M. Legat, K. Strusinska, K. Koziak, D. Nowis, et al.
Inhibition of Cyclooxygenase-2 Indirectly Potentiates Antitumor Effects of Photodynamic Therapy in Mice
Clin. Cancer Res., November 1, 2003; 9(14): 5417 - 5422.
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U. Schmidt-Erfurth, U. Schlotzer-Schrehard, C. Cursiefen, S. Michels, A. Beckendorf, and G. O. H. Naumann
Influence of Photodynamic Therapy on Expression of Vascular Endothelial Growth Factor (VEGF), VEGF Receptor 3, and Pigment Epithelium-Derived Factor
Invest. Ophthalmol. Vis. Sci., October 1, 2003; 44(10): 4473 - 4480.
[Abstract] [Full Text] [PDF]

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D. E. J. G. J. Dolmans, A. Kadambi, J. S. Hill, K. R. Flores, J. N. Gerber, J. P. Walker, I. H. M. B. Rinkes, R. K. Jain, and D. Fukumura
Targeting Tumor Vasculature and Cancer Cells in Orthotopic Breast Tumor by Fractionated Photosensitizer Dosing Photodynamic Therapy
Cancer Res., August 1, 2002; 62(15): 4289 - 4294.
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A. Ferrario, K. von Tiehl, S. Wong, M. Luna, and C. J. Gomer
Cyclooxygenase-2 Inhibitor Treatment Enhances Photodynamic Therapy-mediated Tumor Response
Cancer Res., July 15, 2002; 62(14): 3956 - 3961.
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D. E. J. G. J. Dolmans, A. Kadambi, J. S. Hill, C. A. Waters, B. C. Robinson, J. P. Walker, D. Fukumura, and R. K. Jain
Vascular Accumulation of a Novel Photosensitizer, MV6401, Causes Selective Thrombosis in Tumor Vessels after Photodynamic Therapy
Cancer Res., April 1, 2002; 62(7): 2151 - 2156.
[Abstract] [Full Text] [PDF]

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M. C. Luna, X. Chen, S. Wong, J. Tsui, N. Rucker, A. S. Lee, and C. J. Gomer
Enhanced Photodynamic Therapy Efficacy with Inducible Suicide Gene Therapy Controlled by the grp Promoter
Cancer Res., March 1, 2002; 62(5): 1458 - 1461.
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M. Zheng, M. A. Schwarz, S. Lee, U. Kumaraguru, and B. T. Rouse
Control of Stromal Keratitis by Inhibition of Neovascularization
Am. J. Pathol., September 1, 2001; 159(3): 1021 - 1029.
[Abstract] [Full Text] [PDF]

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Q. Peng, T. Warloe, J. Moan, A. Godal, F. Apricena, K.-E. Giercksky, and J. M. Nesland
Antitumor Effect of 5-Aminolevulinic Acid-mediated Photodynamic Therapy Can Be Enhanced by the Use of a Low Dose of Photofrin in Human Tumor Xenografts
Cancer Res., August 1, 2001; 61(15): 5824 - 5832.
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F. R. Zhang and M. A. Schwarz
Pro-EMAP II is not primarily cleaved by caspase-3 and -7
Am J Physiol Lung Cell Mol Physiol, June 1, 2002; 282(6): L1239 - L1244.
[Abstract] [Full Text] [PDF]

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