Acridine orange (AO) has unique biological actions enabling tumor visualization (fluorovisualization) and a strong cytocidal effect (photodynamic therapy: AO-PDT) under illumination with blue light. Accordingly, in this study, we attempted to develop a new surgical technique for total tumor cell elimination using these photodynamic reactions with AO in a mouse osteosarcoma model. The results showed that local tumor recurrence was significantly inhibited (23%) in the group treated with curettage under fluorovisualization and AO-PDT, compared to that (80%) in the control group treated with curettage alone under ordinary light. Therefore, we concluded that the combination of curettage under fluorovisualization and AO-PDT may be useful for total tumor cell elimination with minimum damage to normal tissue in musculoskeletal sarcomas.

Keywords:
Sarcoma, Osteosarcoma, Acridine orange, Photodynamic therapy, Fluorescence, Fluorovisualization, Local recurrence
1.
Lindner NJ, Ramm O, Hillmann A, Roedl R, Gosheger G, Brinkschmidt C, Juergens H, Winkelmann W: Limb salvage and outcome of osteosarcoma. The University of Münster Experience. Clin Orthop 1999;358:83–89.
2.
Davis AM, Bell RS, Badley EM, Yoshida K, Williams JI: Evaluating functional outcome in patients with lower extremity sarcoma. Clin Orthop 1999;358:90–100.
3.
Shin D-S, Weber KL, Chao EYS, An K-N, Sim FH: Reoperation for failed prosthetic replacement used for limb salvage. Clin Orthop 1999;358:53–63.
4.
Bacci G, Picci P, Ruggieri P, Mercuri M, Avella M, Capanna R, Brach Del Prever A, Mancini A, Gherlinzoni F, Padovani G, Leonessa C, Biagini R, Ferraro A, Ferruzzi A, Cazzola A, Campanacci M: Primary chemotherapy and delayed surgery (neoadjuvant chemotherapy) for osteosarcoma of extremities. The Istituto Rizzoli experience in 127 patients treated preoperatively with intravenous methotrexate (high versus moderate doses) and intraarterial cisplatin. Cancer 1990;65:2539–2553.
5.
Meyers PA, Heller G, Healey J, Huvos A, Lane J, Marcove R, Applewhite A, Valmis V, Rosen G: Chemotherapy for nonmetastatic osteogenic sarcoma. The Memorial Sloan-Kettering experience. J Clin Oncol 1992;10:5–15.
6.
Dougherty TJ, Marcus SL: Photodynamic therapy. Eur J Cancer 1992;28:1734–1742.
7.
Peng Q, Warloe T, Berg K, Moan J, Kongshaug M, Giercksky K-E, Nesland JM: 5-Aminolevulinic acid-based photodynamic therapy. Clinical research and future challenges. Cancer 1997;79:2282–2308.
8.
Lewis MR, Goland PP: In vivo staining and retardation of tumors in mice by acridine compounds. Am J Med Sci 1948;215:282–289.
9.
Korgaonkar KS, Sukhatankar JV: Anti-tumor activity of the fluorescent dye, acridine orange, on Yoshida sarcoma (ascites). Br J Cancer 1963;17:471–473.
10.
Tomson SH, Emmett EA, Fox SH: Photodestruction of mouse epithelial tumors after oral acridine orange and argon laser. Cancer Res 1974;34:3124–3127.
11.
Tomsom SH: Tumor destruction due to acridine orange photoactivation by argon laser. Ann NY Acad Sci 1976;267:191–200.
12.
Tatsuta M, Yamamura H, Yamamoto R, Ichii M, Noguchi S, Iishi H, Mishima H, Hattori T, Okuda S: Destruction of implanted gastric tumors in rats by acridine orange photoactivation with an argon laser. Eur J Cancer Clin Oncol 1984;20:543–552.
13.
Ishikawa S, Nenoto R, Kanoh S, Kobayashi K, Ishizaki S: Photodynamic inactivation of bladder cancer cells (MGH-U1) sensitized with acridine orange and irradiated by argon laser. Tohoku J Exp Med 1984;144:265–271.
14.
Prosser E, Cox D, O’Kennedy R, Carroll K, van der Putten W: Effect of coumarins, haematoporphyrins and acridine orange on the viability and growth of Landshutz ascites tumor cells, in the presence and absence of photoradiation. Cancer Lett 1990;52:71–77.
15.
Bradley DF, Felsenfeld G: Aggregation of an acridine dye on native nad denatured deoxyribonucleates. Nature 1959;184:1920–2921.
16.
Ackerman NB, Shemesh A: Localization of aminoacridine fluorescence in lung 17 tumors of rats. JAMA 1964;187:144–145.
17.
Choi C, Sedlacek RS, Suit HD: Relation-induced osteogenic sarcoma of C3H mouse: Effect of Corynebacterium parvum and WBI in its natural history and response to irradiation. Eur J Cancer 1979;15:433–442.
18.
Takeshita H, Gebhardt MC, Springfield DS, Kusuzaki K, Mankin HJ: Experimental model for the study of drug resistance in osteosarcoma: P-glycoprotein-positive, murine osteosarcoma cell lines. J Bone Joint Surg 1996;78:366–375.
19.
Ovejera AA, Houchens DP, Barker AD: Chemotherapy of human tumor xenografts in genetically athymic mice. Ann Clin Lab Sci 1978;8:50–56.
20.
Lerman LS: Structural considerations in the interaction of DNA and acridines. J Mol Biol 1961;3:18–30.
21.
Kapuscinski J, Darzynkiewicz Z, Melamed MR: Interactions of acridine orange with nucleic acids: Properties of complexes of acridine orange with single stranded ribonucleic acid. Biochem Pharmacol 1983;32:3679–3694.
22.
Amagasa J: Binding of acridine orange to transfer RNA and photodynamic inactivation. J Radiat Res 1986;27:325–338.
23.
Amagasa J: Mechanisms of photodynamic inactivation of acridine orange-sensitized transfer RNA: Participation of singlet oxygen and base damage leading to inactivation. J Radiat Res 1986;27:339–351.
24.
Zelenin AV: Fluorescence microscopy of lysosomes and and related structures in living cells. Nature 1966;212:425–426.
25.
Zdolsek JM, Olsson GM, Brunk UT: Photooxidative damage to lysosomes of culture macrophages by acridine orange. Photochem Photobiol 1990;51:67–76.
26.
Lullmann-Rauch R, Ziegenhagen M: Acridine orange, a precipitant for sulfated glycosaminoglycans, causes mucopolysaccharidosis in cultured fibroblasts. Histochemistry 1991;95:263–268.
27.
Kato A: Gastrofiberscopic diagnosis with acridine orange fluorescence. Gastroenterol Endosc 1970;12:351–362.
28.
Bell RS, O’Connor G, Bell DF, Jacob J: The effect of doxorubicin on local recurrence following marginal resection in the MGH-OGS murine osteosarcoma. Chir Organi Mov 1990;75(suppl 1):67–73.
29.
Uggla AH: The induction of chromosomal aberrations and SCEs by visible light in combination with dyes. II. Cell cycle dependence, and the effect of hydroxyl radical scavengers during light exposure in cultures of Chinese hamster ovary cells sensitized with acridine orange. Mutat Res 1990;231:233–242.
30.
Iwamoto Y, Yoshioka H, Yanagihara Y: Singlet oxygen-producing activity and photodynamic biological effects of acridine compounds. Chem Pharm Bull 1987;35:2478–2483.
31.
Delic J, Coppey J, Magdelenat H, Coppey-Moisan M: Impossibility of acridine orange interaction in nuclear DNA of the living cell. Exp Cell Res 1991;194:147–153.
32.
Zampieri A, Greenberg J: Mutagenesis by acridine orange and proflavin in Escherichia coli strain S. Mutat Res 1965;2:552–556.
33.
McCann J, Choi E, Yamasaki E, Ames BN: Detection of carcinogenesis as mutagens in the Salmonella/microsome test: Assay of 300 chemicals. Proc Natl Acad Sci USA 1975;72:5135–5139.
34.
Van Duuren, Sivak A, Katz C, Melchionne S: Tumorigenicity of acridine orange. Br J Cancer 1969;23:587–590.
35.
Matsumoto N, Yoshiba S: Application of vital staining with acridine orange (AO) to investigation of embryonic growth at the stage of organogenesis. Jikeikai Med J 1989;36:1–9.
36.
Rubbo SD: The influence of chemical constitution on toxicity. I. A general survey of the acridine series. Br J Exp Pathol 1947;28:1–11.
© 2000 S. Karger AG, Basel
2000
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.