【手続補正書】
【提出日】平成17年7月29日(2005.7.29)
【手続補正１】
【補正対象書類名】明細書
【補正対象項目名】００１２
【補正方法】変更
【補正の内容】
【００１２】
イリノテカン（カンプト（登録商標）、カンプトサール（登録商標））はトポイソメラーゼＩ阻害剤である。それは、カンプトテシンの半合成誘導体である。化学名は、（Ｓ）−４，１１−ジエチル−３，４，１２，１４−テトラヒドロ−４−ヒドロキシ−３，１４−ジオキソ−１Ｈ−ピラノ［３’，４’：６，７］−インドリジノール［１，２−ｂ］キノリン−９−イル−［１，４’−ビピペリジン］−１’−カルボキシレート一塩酸塩三水和物である。
【特許文献１】特開2001-247459号公報
【特許文献２】US 5 817 684 / WO 98/42345 / WO 98/25616
【特許文献３】US 5 910 505 / WO 98/42334 / WO 98/25615
【特許文献４】US 5 281 620
【特許文献５】EP 0 743 064 A1 / WO 96/36347
【特許文献６】EP 0 584 001 A1/B1
【特許文献７】WO 94/23753
【特許文献８】WO 95/09621
【特許文献９】WO 97/34482
【特許文献１０】WO 98/25600
【特許文献１１】WO 98/42335
【特許文献１２】WO 98/42332
【特許文献１３】WO 98/42336
【特許文献１４】WO 98/42337
【特許文献１５】WO 98/42346
【特許文献１６】WO 98/42650
【特許文献１７】WO 00/10600 A2 & A3
【特許文献１８】WO 00/16798
【特許文献１９】WO 00/76497
【特許文献２０】WO 01/34135
【特許文献２１】WO 01/34137
【特許文献２２】WO 01/34197
【特許文献２３】WO 01/34198
【特許文献２４】WO 02/09700
【特許文献２５】WO 00/48591
【特許文献２６】US 2001/0027210 A1
【特許文献２７】US 5 620 875
【非特許文献１】Wilson, W., Baguley, B., "Combination of the Antivascular agent DMXAA with Radiation and Chemotherapy", International Journal of Radiation Oncology, Biology and Physics, Vol. 46, no. 3, Feb. 01, 2000, abstract 46, pg 706
【非特許文献２】Kanwar, et al; "Taking lessons from dendritic cells: multiple xenogeneic ligands for leukocyte integrins have the potential to stimulate anti-tumor immunity"; Gene Therapy, 1999; 6:1835-1844.
【非特許文献３】Kanwar et al; "Vascular Attack by 5,6- Dimethylxanthenone-4-acetic Acid Combined with B7.1 (CD80)-mediated Immunotherapy Overcomes Immune Resistance and Leads to the Eradication of Large Tumors and Multiple Tumor Foci1"; Cancer Res., 2001;61: 1948-1956.
【非特許文献４】Hornung et al: "Augmentation of Natural Killer Activity, Induction of IFN and Development Tumor Immunity During The Successful Treatment of Established Murine Renal Cancer Using Flavone Acetic Acid and IL-21.2"; The Journal of Immunology (1988); Vol., 141(10), pp. 3671-3679.
【非特許文献５】Thomsen, et al; "Nitric Oxide Production in Endotoxin-Resistant C3H/HeJ Mice Stimulated with Flavone-8-Acetic Acid and Xanthenone-4-Acetic Acid Analogues"; Biochem. Pharmacol, 43: 11; 1992; pp. 2401-2406.
【非特許文献６】Lash, et al; "Enhancement of the anti-tumor effects of the antivascular agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) by combination with 5-hydroxytryptamine bioreductive drugs"; Br. J. Cancer, 78: pp.439-445, 1998.
【非特許文献７】Hill, Sally A. et al, "Anti-vascular approaches to solid tumour therapy: Evaluation of vinblastine and flavone acetic acid", Int. J. Cancer, Vol. 63, No. 1, pp. 119-123 (1995)
【非特許文献８】Chaplin, D J et al, Proc. Annu. Am. Assoc. Cancer Res, Vol. 37:A3009 (1996)
【非特許文献９】Pruijin; Frederik B et al, "Mechanisms of enhancement if the antitumour activity of melphalan by the tumour-blood-flow inhibitor 5,6-dimethylxanthenone-4-acetic acid", Cancer Chemother Pharmacol, Vol. 39, pp. 541-546 (1997)
【非特許文献１０】Vincent, Patrick W et al, "Chemotherapy with DMXAA (5,6-dimethylxanthenone-4-acetic acid) in combination with CI-1010 (1H-imidazole-1-ethanol, α-[[(2-bromoethyl)amino]methyl]-2-nitro, mono-hydrobromide (R isomer)) against advanced murine colon carcinoma 26", Oncol. Rep., Vol. 4, No.1, pp.143-147 (1997)
【非特許文献１１】Combretastatin Updated: Preliminary Results from Ohio Phase 1 Trial Show Tumors Respond, Patients Experience Vascular Stress, PSA rising: Medical Pike Briefs: Headline Index: Clinical Trial Phase 1 Results, November 8, 1999, available at psa-rising.com/medical/combretastatinupdate.htm.
【非特許文献１２】Pedley, et al; "Enhancement of Antibody-directed Enzyme Prodrug Therapy in Colorectal Xenografts by an Antivascular Agent"; Cancer Res., 59: pp. 3998-4003; 1999
【非特許文献１３】Cliffe, et al; "Combining bioreductive drugs (SR 4233 or SN 23862) with the vasoactive agents flavone acetic acid or 5,6-dimethylxanthenone acetic acid"; Int. J. Radiation Oncology Biol. Phys., 29: pp. 373-377, 1994.
【非特許文献１４】Phillips, R.M; "Inhibition of DT-diaphorase (NAD(P)H:Quinone Oxidoreductase, EC 1.6.99.2) by 5,6-Dimethylxanthenone-4-acetic Acid (DMXAA) and Flavone-8-acetic Acid (FAA): Implications for Bioreductive Drug Development"; Biochem. Pharmacol., 58: pp.303-310, 1999.
【非特許文献１５】Ching, et al; "Effect of thalidomide on tumour necrosis factor production and anti-tumour activity induced by 5,6-dimethylxanthenone-4-acetic acid"; Br. J. Cancer, 72: pp. 339-343, 1995
【非特許文献１６】Browne, et al; "Suppresion of Serum Tumour Necrosis Factor-α by Thalidomide does not Lead to Reversal of Tumour Vascular Collapse and Anti-Tumour Activity of 5,6-Dimethylxanthenone-4-Acetic Acid"; Anticancer Res., 18: pp. 4409-4414, 1998.
【非特許文献１７】Ching, et al; "Interaction of thalidomide, phthalimide analogues of thalidomide and pentoxifylline with the anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid: concomitant reduction of serum tumour necrosis factor-alpha and enhancement of anti-tumour activity"; Br. J. Cancer, 78: pp. 336-343, 1998.
【非特許文献１８】Kestell, et al; "Modulation of the pharmacokinetics of the antitumour agent 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice by thalidomide"; Cancer Chemother. Pharmacol., 46: 135-141, 2000
【非特許文献１９】Cao, et al; "Thalidomide increases both intra-tumoural necrosis factor-α production and anti-tumour activity in response to 5,6-dimethylxanthenone-4-acetic acid"; Br. J. Cancer, 80: pp, 716-723, 1999.
【非特許文献２０】Baguley, et al; "Serotonin involvement in the antitumour and host effects of flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid"; Cancer Chemotherapy. Pharmacol. (1993) 77-81
【非特許文献２１】Zwi, et al; "Correlation Between Immune and Vascular Activities of Xanthenone Acetic Acid Antitumour Agents"; Oncol. Res., 6: pp. 79-85, 1994
【非特許文献２２】Zhao, et al; "Effects of the serotonin receptor antagonist cyproheptadine on the activity and pharmacokinetics of 5,6-dimethylxanthenone-4-acetic acid (DMXAA); Cancer Chemother. Pharmacol., 47: pp. 491-497, 2001.
【非特許文献２３】Futami, et al; "Cytokine Induction and Therapeutic Synergy with Interlukin-2 Against Murine Renal and Colon Cancers by Xanthenone-4-Acetic Acid Derivatives"; J. Immunother., 12: pp. 247-255, 1992.
【非特許文献２４】Ching, et al; "Interaction between endotoxin and the antitumour agent 5,6-dimethylxanthenone-4-acetic acid in the induction of tumour necrosis factor and haemorrhagic necrosis of colon 38 tumours"; Cancer Chemother. Pharmacol., 35: pp. 153-160, 1994.
【非特許文献２５】Ching, et al; "Induction of Intratumoral Tumor Necrosis Factor (TNF) Synthesis and Hemorrhagic Necrosis by 5,6-Dimethylxanthenone-4-Acetic acid (DMXAA) in TNF Knockout Mice1; Cancer Res., 59: pp. 3304-3307, 1999.
【非特許文献２６】Thomsen; et al; "Tumour-dependent Increased Plasma Nitrate Concentrations as an Indication of the Antitumour Eeffect of Flavone-8-acetic Acid and analogues in Mice1; Cancer Res., 51: pp 77-81, 1991.
【非特許文献２７】Baguley, et al; "Evidence that the 5-hydroxytryptamine antagonist, cyproheptadine, modulates nitric oxide production in mice in response to flavone acetic acid, vinblastine and other agents"; In: S., Moncada, M.A., Marletta, J.B., Hibbs, Jr., and E.A. Higgs (eds), Biology of Nitric Oxide Part 2. Enzymology, Biochemistry and Immunology pp. 222-224, London: Portland Press, 1992.
【非特許文献２８】Fujii H, et al; "Vaccination with B7-18 tumor and anti-adhesion therapy with RGD pseudo-peptide (FC-336) efficiently induce anti-metastatic effect"; Clinical & Experimental Metastasis, (1998), Vol. 16, pp. 141-148
【非特許文献２９】Zitvogel, L.; "Interleukin ？12 and b7.1 co-stimulation cooperate in the induction of effective antitumour immunity and therapy of established tumor"; Eur. Journal of Immunology, (1996), Vol. 26, pp. 1335-1341.
【非特許文献３０】Lissoni, P., et al; "Neuroimmunotherapy of advanced solid neoplasms with single evening subcutaneous injection of low-dose interleukin-2 and melatonin: preliminary results"; European Journal of Cancer, (1993), Vol. 29A(2), pp. 185-189
【非特許文献３１】Nawrocki, S., and Mackiewicz A., "Genetically modified tumour vaccines-where we are today", Cancer Treatment Reviews, (1999), Vol. 25, pp. 29-46
【非特許文献３２】Thrash-Bingham, C.A. and Tartof, K.D., "aHIF: A natural antisense transcript overexpressed in human renal cancer during hypoxia"; Journal of the National Cancer Institute,, (1999), Vol. 91(2),  pp. 143-151
【非特許文献３３】Rustin, G.; "Vascular Targeting in the Clinic"; Abstract; ICTR 2000: 1st Int'l Conference on Translational Research A.
【非特許文献３４】Baguley, B.C., et al; "291 Mechanisms of tumour blood flow inhibition by the antitumour drug DMXAA (5,6-dimethylxanthenone-4-acetic acid"; Preceedings of the 11th NCI EORTC AACR Symposium; Published as a supplement to Clinical Cancer Research, Vol. 6, November 2000
【非特許文献３５】Zhou, et al; Caplus 2001:422777; "A difference between the rat and mouse in the pharmacokinetic interaction of 5,6-*** dimethylxanthenone***-4-acetic acid with thalidomide"; Cancer Chemother. Pharmacol. (2001), 47(6), 541-544
【非特許文献３６】Zhou, et al; Caplus; 2001:352622; "Determination of unbound concentration of the novel … liquid chromatography with fluorimetric detection; J. Chromatogr., B: (2001), 757(2), 359-363
【非特許文献３７】Zhou, et al; Caplus 2001:352620; "Determination of the covalent adducts … samples by high-performance liquid chromatography; J. Chromatogr., B: (2001), 757(2), 343-348
【非特許文献３８】Zhou, et al; Caplus 2001:348171; "Reversible binding of the novel anti-tumour agent … and its distribution into blood cells in various species"; J. Pharmacy and Pharmacology. (2001), 53(4), 463-471
【非特許文献３９】Zhou, et al; Caplus 2001:324235; "In vitro and in vivo kinetic interactions … -4-acetic acid with thalidomide and diclofenac"; Cancer Chemother. Pharmacol. (2001), 47(4), 319-326.
【非特許文献４０】Cao, et al; Caplus 2001:183669; "Interferon-indicuble protein 10 induction and inhibition of angiogenesis in vivo by the antitumour agent 5,5-dimethylxanthenone-4-acetic acid (DMXAA)"; Cancer Res. (2001), 61(4), 1517-1521
【非特許文献４１】Murata, et al; Caplus 2001:175425; "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"; Int. J. Radiat. Biol. (2001), 77(2), 195-204
【非特許文献４２】Zhou, et al; Caplus 2000:860808; "Identification of the human liver cytochrome P450 isoenzyme responsible for the 6-methylhydroxylation of the novel anticancer drug 5,6-dimethylxanthenone-4-acetic acid"; Drug Metab. Dispos. A Publication of The American Soc. for Pharma. and Exper. Therap.; (2000), 28(12), 1449-1456
【非特許文献４３】Siim, et al; Caplus 2000:642218; "Scintigraphic imaging of the hypoxia marker 99mtechnetium-labeled 2,2'-(1,4-Diaminobutane)bis(2-methyl-3-butanone) Dioxime (99mTc-labeled HL-91;Prognox): Noninvasive Detection of Tumour Response to the Antivascular Agent 5,6-dimethylxanthenone-4-acetic acid"; Cancer Res. (2000), 60(16), 4582-4588.
【非特許文献４４】Aitken, et al; Caplus 2000:459208; "Synthesis and antitumour activity of new derivatives of flavone-8-acetic acid (FAA). Part 4: variation of the basic structure"; Arch. Pharm. Pharm. Med. Chem. (Weinheim, Ger.) (2000), 333(6), 181-188
【非特許文献４５】Zhou, et al; Caplus 1999:765284; "Determination of two major metabolites of the novel anti-tumour agent 5,6-dimethylxanthenone-4-acetic acid in hepatic microsomal incubations by high-performance liquid chromatography with fluoresence detection"; J. Chromatography., B: (1999), 734(1), 129-136.
【非特許文献４６】Ching, et al; Caplus 1999:538562; "Induction of STAT and NF.kappa.B activation by the antitumour agents 5,6-dimethylxanthenone-4-acetic acid and flavone acetic acid in a murine macrophage cell line"; Biochemical. Pharmacology. (1999), 58(7), 1173-1181.
【非特許文献４７】Kestell, et al; Caplus 1999:191815; "Plasma disposition, metabolism, and excretion of the experimental antitumour agent 5,6-dimethylxanthenone-4-acetic acid in the mouse, rat and rabbit"; Cancer Chemother. Pharmacol. (1999), 43(4), 323-330.
【非特許文献４８】Joseph, et al; Caplus 1999:109860; "Stimulation of tumors to synthesize tumor necrosis factor-α in situ using 5,6-dimethylxanthenone-4-acetic acid: a novel approach to cancer therapy"; Cancer Res. (1999), 59(3), 633-638.
【非特許文献４９】Wilson, et al; Caplus 1999:5894; "Enhancement of tumor radiation response by the antivascular agent 5,6-dimethylxanthenone-4-acetic acid"; Int. J. Radiat. Oncol., Biol., Phys. (1998), 42(4), 905-908
【非特許文献５０】Zaks-Zilberman, et al; Caplus 1998:649593; "Induction of adrenomedullin MrNA and protein by lipopolysaccharide and paclitaxel (taxol) in murine macrophages"; Infection and Immunity. (1998), 66(10), 4669-4675.
【非特許文献５１】Pang, et al; Caplus 1998:534308; "Antitumor activity of the novel immune modulator 5,6-dimethylxanthenone-4-acetic acid (DMXAA) in mice lacking the interferon-gamma receptor"; Eur. J. Cancer (1998), 34(8), 1282-1289.
【非特許文献５２】Baguley, et al; Caplus 1998:426219; "Immunomodulatory actions of xanthenone anticancer agents"; BioDrugs (1997), 8(2), 119-127.
【非特許文献５３】Siim, et al; Caplus 1998:145311; "Nitro reduction as an electronic switch for bioreductive drug activation"; Oncology Research. (1997), 9(6/7), 357-369.
【非特許文献５４】Baguley, et al; Caplus 1998:145286; "Increased plasma serotonin following treatment with flavone-8-acetic acid, 5,6-dimethylxanthenone-4-acetic acid, vinblastine, and colchicine: relation to vascular effects"; Oncology Research. (1997), 9(2), 55-60.
【非特許文献５５】Moilanen, et al; Caplus 1998:109247; "Persistant induction of nitric oxide synthase in tumors from mice treated with the anti-tumor agent 5,6-dimethylxanthenone-4-acetic acid"; Br. J. Cancer (1998), 77(3), 426-433.
【非特許文献５６】Philpott, et al; Caplus 1998: 43376; "Production of tumor necrosis factor-α by cultured human peripheral blood leukocytes in response to the anti-tumour agent, 5,6- ***dimethylxanthenone*** -4-acetic acid (NSC 640488)"; Br. J. Cancer (1997), 76(12), 1586-1591.
【非特許文献５７】Everett, et al; Caplus 1997:419257; "High-performance ion chromatography applied to free-radical mechanisms in drug design. The problem of ion analysis at high ionic strengths"; J. of Chromatography A (1997), 770(12), 273-279.
【非特許文献５８】Patel, et al; Caplus 1997:198501; "The effect of 5,6-dimethylxanthenone-4-acetic acid on tumor necrosis factor production by human immune cells"; Anticancer Research. (1997), 17 (1A), 141-150.
【非特許文献５９】Miners, et al; Caplus 1997:71622; "Preclinical prediction of factors influencing the elimination of 5,6-dimethylxanthenone-4-acetic acid, a new anticancer drug"; Cancer Research. (1997), 57(2), 284-289.
【非特許文献６０】Watts, et al; Caplus 1996:492701; "Changes in coagulation and permeability properties of human endothelial cells in vitro induced by TNF-α or 5,6 MeXAA; British. J. of Cancer (Suppl. XXVII) (1996), 74(27), S164-S167.
【非特許文献６１】Wilson, et al; Caplus 1996-492687; "Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N"; British J. of Cancer (Suppl. XXVII) (1996), 74(27), S43-S47.
【非特許文献６２】Pedley, et al; Caplus 1996:432950; "Ablation of colorectal xenografts with combined radioimmunotherapy and tumor blood flow-modifying agents"; Cancer Research. (1996), 56(14), 3293-3300.
【非特許文献６３】Wilson, et al; Caplus 1995:953723; "Hypoxia-activated prodrugs as antitumor agents: strategies for maximizing tumor cell killing"; Clinical and Experimental Pharmacology and Physiology. (1995), 22(11), 881-885.
【非特許文献６４】Philpott, et al; Caplus 1995:724307; "Induction of tumor necrosis factor-.alpha. by single and repeated doses of the antitumor agent 5,6-dimethylxanthenone-4-acetic acid"; Cancer Chemother. Pharmacol. (1995), 36(2), 143-8.
【非特許文献６５】Laws, et al; Caplus 1995:674435; "Preclinical in vitro and in vivo activity of 5,6-dimethylxanthenone-4-acetic acid"; British J. of Cancer (1995), 71(6), 1204-9.
【非特許文献６６】Webster, et al; Caplus 1995-443204; "Metabolism and elimination of 5,6-dimethylxanthenone-4-acetic acid in the isolated perfused rat liver"; Drug Metab. Dispos. A Publication of the Am. Soc. for Pharm. and Exper. Therapeutics; (1995), 23(3), 363-8.
【非特許文献６７】Perera, et al; Caplus 1995:223939; "Activation of LPS-inducible genes by the antitumor agent 5,6-dimethylxanthenone-4-acetic acid in primary murine macrophages. Dissection of signalling pathways leading to gene induction and tyrosine phosphorylation"; J. Immunol. (1994), 153(10), 4684-4693.
【非特許文献６８】Zwi, et al; Caplus 1995:197516; "The morphological effect of the anti-tumor agents flavone acetic acid and 5,6-dimethyl xanthenone acetic acid on the colon 38 mouse tumor; Pathology (1994), 26(2), 161-169.
【非特許文献６９】Kestell, et al; Caplus 1994:644972; "Disposition of the novel antitumour agent  xanthenone-4-acetic acid in the mouse: identification of metabolites and routes of elimination"; Xenobiotica (1994), 24(7), 635-647.
【非特許文献７０】Pedley, et al; Caplus 1994:599737; "Enhancement of radioimmunotherapy by drugs modifying tumour blood flow in a colonic xenograft model"; Int. J. Cancer (1994), 57(6), 830-5.
【非特許文献７１】Baguley, et al; Caplus 1994:595115; "Serotonin involvement in the antitumor and host effects of flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid"; Cancer Chemother. Pharmacol. (1993), 33(1), 77-81.
【非特許文献７２】Everett, et al; Caplus 1994:499154; "Decarboxylation of the antitumor drugs flavone-8-acetic acid and xanthenone-4-acetic acid by nitrogen dioxide"; Anti-Cancer Drug Design. (1994), 91(1), 68-72.
【非特許文献７３】Ching, et al; Caplus 1994:315345; "Effect of tumor growth on the macrophage response to the antitumor agent 5,6-dimethylxanthenone-4-acetic acid"; Anticancer Research. (1993), 13(6A), 2069-2076.
【非特許文献７４】Ching, et al; Caplus 1994:208087; "Induction of tumor necrosis factor-α messenger RNA in human and murine cells by the flavone acetic acid analog 5,6-dimethylxanthenone-4-acetic acid (NSC 640488)"; Cancer Research. (1994), 54(4), 870-872.
【非特許文献７５】Thomsen, et al; Caplus 1994:124393; "Nitric oxide: its production in host-cell-infiltrated EMT6 spheroids and its role in tumor cell killing by flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid"; Cancer Chemother. Pharmacol. (1992), 31(2), 151-155.
【非特許文献７６】Veszelovszky, et al; Caplus 1993:204708; "Flavone acetic acid and 5,6-dimethylxanthenone-4-acetic acid: relationship between plasma nitrate elevation and the induction of tumor necrosis": Eur. J. Cancer, Part A (1993), 29A(3), 404-408.
【非特許文献７７】Gamage, et al; Caplus 1993:80787; "Structure-activity relationship for substituted 9-oxo-9,10-dihydroacridine-4-acetic acids: analogs of the colon tumor active agent xanthenone-4-acetic acid"; Anti-Cancer Drug Design. (1992), 7(5), 403-414.
【非特許文献７８】Ching, et al; Caplus 1992:604666; "Antitumor responses to flavone-8-acetic acid and 5,6-dimethylxanthenone-4-acetic acid in immune-deficient mice"; Br. J. Cancer (1992), 66(1), 128-130.
【非特許文献７９】Ching, et al; Caplus 1992:503777; "Stimulation of macrophage tumoricidal activity by 5,6-dimethyl xanthenone-4-acetic acid, a potent analog of the antitumour agent flavone-8-acetic acid"; Biochemical Pharmacology. (1992), 44(1). 192-195.
【非特許文献８０】Thomsen, et al; Caplus 1992-203711; "Nitric oxide production in endotoxin-resistant C3H/HeJ mice stimulated with flavone-8-acetic acid and xanthenone-4- acetic acid analogs"; Biochemical Pharmacology. (1992), 43(11), 2401-2406.
【非特許文献８１】Thomsen, et al; Caplus 1992:165869; "Modulation of superoxide production from murine macrophages by the antitumor agent flavone acetic acid and xanthenone acetic acid analogs; Biochemical Pharmacology. (1992), 43(2), 386-389.
【非特許文献８２】Ching, et al; Caplus 1992:243202; "In vitro methods for screening agents with an indirect mechanism of antitumor activity: xanthenone analogs of flavone acetic acid"; Eur. J. Cancer (1991), 27(12), 1684-1689.
【非特許文献８３】Ching, et al; Caplus 1992:51034; "Hemotological effects in mice of the antitumor agents xanthenone-4-acetic acid, 5,6-methyl xanthenone-4-acetic acid and flavone acetic acid"; Cancer Chemother. Pharmacol. (1991), 28(6), 414-419.
【非特許文献８４】McKeage, et al; Caplus 1992:15300; "Plasma  pharmacokinetics of the antitumor agents 5,6-dimethylxanthenone-4-acetic acid, xanthenone-4-acetic acid and flavone-8-acetic acid in mice"; Cancer Chemother. Pharmacol. (1991) 28(6), 409-413.
【非特許文献８５】Rewcastle, et al; Caplus 1991:535875; "Potential antitumor agents. 63. Structure-activity relationships for side-chain analogs of the colon 38 active agent 9-oxo-9H-xanthene-4-acetic acid"; J. Med. Chem. (1991), 34(9), 2864-2870.
【非特許文献８６】Zwi, et al; Caplus 1991:526486; "Necrosis in nontumor tissues caused by flavone acetic acid and 5,6-dimethylxanthenone acetic acid"; Br. J. Cancer (1990), 62(6), 932-934.
【非特許文献８７】Ching, et al; Caplus 1991:441427; "Induction of natural killer activity by xanthenone analogs of flavone acetic acid: relation with antitumor activity": Eur. J. Cancer (1991), 27(1), 79-83
【非特許文献８８】Kestell, et al; Caplus 1991:177788; Determination of xanthenone-4-acetic acid in mouse plasma by high-performance liquid chromotography"; J.of Chromatography. (1991), 564(1), 315-321.
【非特許文献８９】Thomsen, et al; Caplus 1991:74808; "Evidence for the production of nitric oxide by activated macrophages treated with the antitumor agents flavone-8-acetic acid and xanthenone-4-acetic acid"; Cancer Research. (1990), 50(21), 6966-6970.
【非特許文献９０】Rewcastle, et al; Caplus 1991:35415; "Potential antitumor agents. 61. Structure-activity relationships for in vivo colon 38 activity among distrubuted 9-oxo-9H-xanthene-4-acetic acids"; J. Med. Chem. (1991), 34(1), 217-222.
【非特許文献９１】Rewcastle, Gordon W.; Caplus 1990:631318; "Synthesis and development of two new classes of anticancer drugs, the tricyclic carboxamides and the xanthenoneacetic acids"; Chemistry in New Zealand. (1989), 53(6), 145-150.
【非特許文献９２】Rewcastle, et al; Caplus 1990:503264; "Light-induced breakdown of flavone acetic acid and xanthenone analogs in solution"; J. Natl. Cancer Inst. (1990), 82(6), 528-529.
【非特許文献９３】Atwell, et al; Caplus 1990:91211; "Synthesis and antitumor activity of topologically-related analogs of flavvoneacetic acid"; Anti-Cancer Drug Design. (1989), 4(2), 161-169.
【非特許文献９４】Van der Auwera, et al; Caplus 1989:554340; "Conformational features of four model tripeptides having Piv-Pro-MeXaa-Nme2 sequences"; Bull. Soc. Chim.Belg.; (1988), 97(3), 199-207.
【非特許文献９５】Rewcastle, et al; Caplus 1989:173045; "Potential antitumor agents. 58. Synthesis and structure-activity relationships of substituted xanthenone-4-acetic acids active against the colon 38 tumor in vivo"; J. Med. Chem. (1989), 32(4), 793-799.
【非特許文献９６】Siemann, D W; Mercer, E; Lepler, S; Rojiani, A M: "Vascular targeting Agents Enhance Chemotherapeutic Agent Activities in Solid Tumor Therapy" International Journal of Cancer, vol.99, 2002, pages 1-6.
【非特許文献９７】Rewcastle, G.W. et al., "Potential Antitumor Agents. 62. Structure-Activity Relationships for Tricyclic Compounds Related to the Colon Tumor Active Drug 9-Oxo-9H-xanthene-4-acetic acid" Journal of Medicinal Chemistry (1991), 34(2): 491-496.
【非特許文献９８】Atwell, et al., "Potential Antitumor Agents. 60. Relationships between structure and in vivo colon 38 activity for 5-substituted 9-oxoxanthene-4-acetic acids", Journal of Medicinal Chemistry (1990) 33(5): 1375-1379.
【非特許文献９９】Griffioen, A.W., Damen, C.A., Mayo, K.H., Barendsz-Janson, A.F., Mertinotti, S., Blijham, G.H., and Groeneegen, G. "Angiogenesis inhibitors overcome tumor induced endothelial cell anergy". Int. J. Cancer,  80: 315-319, 1999.
【非特許文献１００】O'Reilly, M.S., Boehm, T., Shing, Y., Fukai, N., Vasios, G., Lane, W.S., Flynn, E., Birkhead, J.R., Olsen, B.R., and Folkman, J. "Endostatin: An endogenous inhibitor of angiogenesis and tumour growth". Cell, 88: 277-285, 1997.
【非特許文献１０１】Corbett, T.H., Bissery, M.C., Wozniak, A., Polin, J., Tapazoglou, E., Dieckman, J., and Valeriote, F. "Activity of flavone acetic acid (NSC-347512) against solid tumors of mice". Investigational New Drugs, 4:207-220, 1986.
【非特許文献１０２】Shoemaker, R., Wolpert-DeFilippes, M., Plowman, J., Abbott, B., Venditti, J., Trader, M., Griswold, D., Gerlach, J., and Ling, V. "Pleiotropic resisitance and drug development". Progress Clin. Biol. Res., 223: 143-149, 1986.
【非特許文献１０３】Zaharko, D.S., Grieshaber, C.K., Plowman, J., and Cradock, J.C. "Therapeutic and pharmacokinetic relationships of flavone acetic acid: an agent with activity against solid tumors". Cancer Treatment Reports, 70: 1415-1421, 1986.
【非特許文献１０４】Plowman, J., Narayanan, V.L., Dykes, D., Szarvasi, E., Briet, P., Yoder, O.C., and Paull, K.D. "Flavone acetic acid: a novel agent with preclinical antitumour activity against colon adenocarcinoma 38 in mice". Cancer Treatment Reports, 70:631-635, 1986.
【非特許文献１０５】Bibby, M.C., and Double, J.A. "Flavone acetic acid-from laboratory to clinic and back". Anti-Cancer Drugs, 4: 3-17, 1993.
【非特許文献１０６】Ching, L.-M., and Baguley, B.C., "The anti-tumor and immune-modulatory activities of flavone acetic acid and xanthone acetic acids". In: N.P., Das (ed.), flavanoids in Biology and Medicine. III.. Proceedings of the 3rd International Symposium on Flavonoids in Biology and Medicine pp. 381-391. Singapore; National University of Singapore, 1989.
【非特許文献１０７】Bibby, M.C., Double, J.A., Loadman, P.M. and Duke, C.V. "Reduction of tumor blood flow by flavone acetic acid: a possible component of therapy". J. Natl. Cancer Inst. 81: 216-220, 1989.
【非特許文献１０８】Zwi, L.J., Baguley, B.C., Gavin, J.B. and Wilson, W.P. "Blood flow failure as a major determinant in the antitumour action of flavone acetic acid". J. Natl. Cancer Inst. 81: 1005-1013, 1989.
【非特許文献１０９】Jameson MB, Thompson PI, Baguley B.C, et al. "Phase I pharmacokinetic and pharmacodynamic study of 5,6-dimethylxanthenone-4-acetic acid (DMXAA), a novel antivascular agent". Proc Am Soc Clin Oncol 2000, 19, 182a
【非特許文献１１０】Showalter, H. H. Hollis; Chemtracts: Org.Chem. (1991), 4(2), pages 168-171; "Potential antitumour agents.61. Structure-activity relationships for in vivo colon 38 activity among distributed 9-oxo-9H-xanthene-4-acetic acid". CAPLUS 1991:491965: abstract
【非特許文献１１１】Pruijn FB, van Daalen M, Holford NH,Wilson WR, "Mechanisms of enhancement of the antitumour activity of melphalan by the tumour-blood-flow inhibitor 5,6-dimethylxanthenone-4-acetic acid", Cancer Chemother Pharmacol, 1997;39 (6):541-6.
【非特許文献１１２】Siemann DE, Mercer E, Lepler S, Rojiani AM, "Vascular targeting agents enhance chemotherapeutic agent activities in solid tumor therapy", Int J Cancer.2002 May 1;99 (1):1-6.
【非特許文献１１３】Zhou S, Chin R, Kestell P, Tingle MD, Paxton JW. "Effects of anticancer drugs on the metabolism of the anticancer drug 5-6-dimethylxanthenone-4-acetic (DMXAA) by human liver microsomes". Br J Chin Pharmacol.2001 Aug;52(2):129-36.
【非特許文献１１４】B.G. Wouters, S.A. Weppler, M. Koritzinsky, W. Landuyt1, S. Nuyts1, J. Theys, R.K. Chiu, P.Lambin, "Hypoxia as a target for combined modality treatments" European Journal of Cancer, 38 (2002) 240-257.
【非特許文献１１５】Rustin G, Galbraith S, Taylor N, et al, "Impact on tumour perfusion measured by dyanamic magnetic resonance imaging (MRI), the phase 1 trial of 5,6-dimethylxanthenone-4-acetic acid (DMXAA)". Proc 10th NCI-EORTC Symp New Drugs, 1998, 10, 126