Complexes of gallium(III) and other metal ions and their potential in the treatment of neoplasia

Bibliography

• FICHTINGER-SCHEPMAN AMJ, VAN DER VEER JL, DENHARTOG JHJ et al.: Adducts of the antitumour drug cis-diamminedichloroplatinum(II) with DNA: formation, identification and quantification. Biochem-istry (1985) 24:707–713.
   Google Scholar
• BURGER RM, ADLER AD, HORWITZ SB, MIMS WB,PEISACH J: Demonstration of nitrogen coordination in metal-bleomycin complexes by electron spin-echo envelope spectroscopy. Biochemistry (1 9 8 1) 20:1701-1704.
   Google Scholar
• MAY PM, WILLIAMS GK, WILLIAMS DR: Speciationstudies of adriamycin, quelamycin and their metal complexes. Inorg. Chim. Acta (1980) 46:221–228.
   Web of Science ®Google Scholar
• HASINOFF BB, DAVEY JP: The iron(III)-adriamycin complex inhibits cytochrome c oxidase before its inactivation. Biochem. J. (1998) 250:827–834.
   Google Scholar
• ROSENBERG B, VANCAMP L: The successful regression of large solid sarcoma 180 tumors by platinum compounds. Cancer Res. (1970) 30:1799–1802.
   PubMed Web of Science ®Google Scholar
• GRAHAM RD, WILLIAMS DR: The synthesis and screening for anti-bacterial, -cancer,-fungicidal and -viral activities of some complexes of palladium and nickel./ Inorg. Nucl. Chem. (1979) 41:1245–1249.
   Web of Science ®Google Scholar
• MYETTE MS, ELFORD HL, CHITAMBAR CR: Interaction of gallium nitrate with other inhibitors of ribonucleotide reductase: effects on the proliferation of human leukemic cells. Cancer Lea. (1998) 129:199–204.
   PubMed Web of Science ®Google Scholar
• LARSON SM, RASEY JS, ALLEN DR et al.: Commonpathway for tumor cell uptake of gallium-67 and iron-59 via a transferrin receptor. J. Natl. Cancer Inst. (1980) 64:41–53.
   PubMed Web of Science ®Google Scholar
• ERCK A, RAINEN L, WHILEYMAN J, CHANG I-M, KIMBALLAP, BEAR J: Studies of rhodium(ll) carboxylates as potential anti-tumor agents. Proc. Soc. Exp. Biol. Med. (1974) 145:1278–1283.
   PubMed Web of Science ®Google Scholar
• SARYAN LA, ANKEL E, KRISHNAMURTI C, PETERING DH,ELFORD H: Comparative cytotoxic and biochemical effects of ligands and metal complexes of alpha-N-heterocyclic carboxaldehyde thiosemicarbazones. J. Med. Chem. (1979) 22:1218–1221.
   PubMed Web of Science ®Google Scholar
• BOOTH B, SARTORELLI A: Synergistic interaction ofkethoxal bis(thiosemicarbazone) and cupric ions in sarcoma 180. Nature (1966) 210:104–105.
   PubMed Web of Science ®Google Scholar
• BOOTH B, DONELLY T, ZETTNER A, SARTORELLI A: Metabolic effects of zinc in intact cells-comparative studies of zinc chloride and the zinc chelate of kethoxal bis(thiosemicarbazone). Biochem. Pharmacol. (1971) 20:3109–3118.
   PubMed Web of Science ®Google Scholar
• LIPPARD SJ: Platinum, Gold and Other Metal Chemothera-peutic Agents. American Chemical Society, Washington DC, USA (1983).
   Google Scholar
• NICOLINI M: Proceedings of the 5th InternationalSymposium on Platinum and other Metal Co-ordination Compounds in Cancer Chemotherapy. Nijhoff Publishing, Boston, USA (1988).
   Google Scholar
• KEPPLER BK: Metal Complexes in Cancer Chemotherapy. VCH Verlagsgesellschaft, Weinheim, Germany (1993).
   Google Scholar
• KELLAND LR (Ed.): Meeting report on 8th international symposium on platnium and other metal coordina-tion compounds in cancer chemotherapy. J. Inorg. Biochem. (1999) 77.
   Google Scholar
• •Recent update on developments in the field of metal chemotherapeutics.
   Google Scholar
• HARRIS WR, PECORARO VL: Thermodynamic binding constants for gallium transferrin. Biochemistry (1983) 22:292–299.
   PubMed Web of Science ®Google Scholar
• HARRIS AW, SEPHTON RG: Transferrin promotion of67Cra and 59Fe uptake by cultured mouse myeloma cells. Cancer Res. (1977) 37:3634–3638.
   PubMed Web of Science ®Google Scholar
• LARSON SM, RASEY JS, ALLEN DR et al.: Common pathway for tumor cell uptake of gallium-67 and iron-59 via a transferrin receptor. J. Natl. Cancer Inst. (1980) 64:41–53.
   PubMed Web of Science ®Google Scholar
• CHITAMBAR CR, SELIGMAN PA: Effects of different transferrin forms on transferrin receptor expression, iron uptake and cellular proliferation of human leukemic HL60 cells: Mechanisms responsible for the specific cytotoxicity of transferrin-gallium. J. Clin. Invest. (1986) 78:1538–1546.
   PubMed Web of Science ®Google Scholar
• RICHARDSON DR, PONKA P: The molecular mechanisms of the metabolism and transport of iron in normal and neoplastic cells. Biochim. Biophys. Acta (1997) 1331:1–40.
   PubMed Web of Science ®Google Scholar
• ••Comprehensive review of the metabolism of a very biologi-cally significant essential element.
   Google Scholar
• GUNSHIN H, MACKENZIE B, BERGER UV et al.: Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature (1997) 388:482–488.
   PubMed Web of Science ®Google Scholar
• FLEMING MD, TRENOR CC, SU MA et al.: Microcytic anemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nature Genet. (1997) 16:383–386.
   PubMed Web of Science ®Google Scholar
• FLEMING MD, ROMANO MA, SU MA, GARRICK LM, GARRICK MD, ANDREWS NC: Nramp2 is mutated in the anemic Belgrade (b) rat: Evidence of a role for Nramp2 in endosomal iron transport. Proc. Natl. Acad. Sci. USA (1998) 95:1148–1153.
   PubMed Web of Science ®Google Scholar
• GUTIERREZ JA, YU J, RIVERA S, WESSLING-RESNICK M: Functional expression cloning and characterization of SF1', a stimulator of Fe transport. J. Cell Biol. (1997) 139:895–905.
   PubMed Web of Science ®Google Scholar
• CHITAMBAR CR, SAX D: Regulatory effects of gallium on transferrin-independent iron uptake by human leukemic HL60 cells. Blood (1992) 80:505–511.
   PubMed Web of Science ®Google Scholar
• KAPLAN J, JORDAN I, STURROCK A: Regulation of the transferrin-independent iron transport system in cultured cells. J. Biol. Chem. (1991) 266:2997–3004.
   PubMed Web of Science ®Google Scholar
• BAKER E, RICHARDSON DR, GROSS S, PONKA P: Evaluation of the iron chelation potential of pyridoxal, salicylaldehyde and 2-hydroxy-1-naphthylaldehyde using the hepatocyte in culture. Hepatology (1992) 15:492–501.
   PubMed Web of Science ®Google Scholar
• RICHARDSON DR, PONKA P: Identification of a mechanism of iron uptake by cells which is stimulated by hydroxyl radicals generated via the Haber-Weiss reaction. Biochim. Biophys. Acta (1995) 1269:105–114.
   PubMed Web of Science ®Google Scholar
• RICHARDSON DR, CHUA A, BAKER E: Activation of aniron-transport mechanism from transferrin in hepatocytes by preincubation with low molecular weight iron complexes. J. Lab. Clin. Med. (1999) 133:144–151.
   PubMed Web of Science ®Google Scholar
• CHITAMBAR CR, MATTHAEUS WG, ANTHOLINE WE, GRAFF K, O'BREIN WJ: Inhibition of leukemic HL60 cell growth by transferrin-gallium: Effects on ribonudeo-tide reductase and demonstration of drug synergy with hydroxyurea. Blood (1988) 72: 1930-1936.
   Google Scholar
• CHITAMBAR CR, NARASIMHAN J, GUY J, SEM DS, O'BREIN WJ: Inhibition of ribonucleotide reductase by gallium in murine leukemic L1210 cells. Cancer Res. (1991) 51:6199–6201.
   PubMed Web of Science ®Google Scholar
• SELIGMAN PA, SCHLEICHER RB, SIRIWARDANA G, DOMENICO J, GELFAND EW: Effects of agents that inhibit cellular iron incorporation on bladder cell proliferation. Blood (1993) 82:1608–1617.
   PubMed Web of Science ®Google Scholar
• CHITAMBAR CR, ZIVKOVIC Z: Uptake of gallium-67 byhuman leukemic cells: Demonstration of transferrin-receptor-dependent and transferrin-independent mechanisms. Cancer Res. (1987) 47:3929–3934.
   PubMed Web of Science ®Google Scholar
• CHITAMBAR CR, WERELEY JP: Resistance to the antitumor agent gallium nitrate in human leukemic cells is associated with decreased gallium/iron uptake, increased activity of iron regulatory protein-1 and decreased ferritin production. J. Biol. Chem. (1997) 272:12151–12157.
   PubMed Web of Science ®Google Scholar
• WARRELL RP JR, COONLEY CJ, STRAUS DJ, YOUNG CW:Treatment of patients with advanced malignant lymphoma using gallium nitrate administered as a seven-day continuous infusion. Cancer (1983) 51:1982–1987.
   PubMed Web of Science ®Google Scholar
• CHITAMBAR CR, ZAHIR SA, RITCH PS, ANDERSON T: Evaluation of continuous-infusion gallium nitrate and hydroxyurea in combination for the treatment of refractory non-Hodgkin's lymphoma. Am. J. Clin. Oncol. (1997) 20:173–178.
   PubMed Web of Science ®Google Scholar
• CRAWFORD ED, SAIERS JH, BAKER LH, COSTANZI JH,BUKOWSKI RM: Gallium nitrate in advanced bladder carcinoma: southwest oncology group study. Urology (1991) 38:355–357.
   PubMed Web of Science ®Google Scholar
• CHANG AY, TU ZN, SMITH JL et al.: Phase II trial of gallium nitrate, amonafide and teniposide in metastatic non small cell lung cancer. An eastern cooperative oncology group study (E2588). Invest. New Drugs (1995) 13:137–141.
   Google Scholar
• RICHARDSON DR, TRAN E, PONKA P: The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective antiproliferative agents.Blood (1995) 86:4295–4306.
   PubMed Web of Science ®Google Scholar
• •Landmark paper describing the potential of the PIH class of compounds as antineoplastic agents.
   Google Scholar
• RICHARDSON DR, MILNES K: The potential of iron chelators of the pyridoxal isonicotinoyl hydrazone class as effective anti-proliferative agents II: The mechanism of action of ligands derived from salicylal-dehyde benzoyl hydrazone and 2-hydroxy-l-naphthylaldehyde benzoyl hydrazone. Blood (1997) 89:3025–3038.
   PubMed Web of Science ®Google Scholar
• DARNELL G, RICHARDSON DR: The potential of analogues of the pyridoxal isonicotinoyl hydrazone class as effective anti-proliferative agents BI: The effect of the ligands on molecular targets involved in prolif-eration. Blood (1999) 94:781–792.
   PubMed Web of Science ®Google Scholar
• PONKA P, SCHULMAN HM, WILCZYNSKA A: Ferric pyridoxal isonicotinoyl hydrazone can provide iron for heme synthesis in reticulocytes. Biochim. Biophys. Acta (1982) 718:151–156.
   PubMed Web of Science ®Google Scholar
• LANDSCHULZ W, THESLEFF I, EKBLOM P: A lipophiliciron chelator can replace transferrin as a stimulator of cell proliferation and differentiation. J. Cell Biol. (1984) 98:596–601.
   PubMed Web of Science ®Google Scholar
• SARTORELLI AC, BOOTH BA: Inhibition of the growth ofsarcoma 180 ascites cells by combinations of inhibi-tors of nucleic acid biosynthesis and cupric chelate of kethoxal bis-(thiosemicarbazone). Cancer Res. (1967) 27:1614–1619.
   PubMed Web of Science ®Google Scholar
• KNORR GM, CHITAMBAR CR: Gallium pyridoxal isonicotinoyl hydrazone (Ga-1111), a novel cytotoxic gallium complex. A comparative study with gallium nitrate. AntiCancer Res. (1998) 18:1733–1738.
   PubMed Web of Science ®Google Scholar
• CHITAMBAR CR, BOON P, WERELEY JP: Evaluation of transferrin and gallium-pyridoxal isonicotinoyl hydrazone as potential therapeutic agents to overcome lymphoid leukemic cell resistance to gallium nitrate. Clin. Cancer Res. (1996) 2:1009–1015.
   PubMed Web of Science ®Google Scholar
• HENTZE MW, KOHN LC: Molecular control of vertebrate iron metabolism: mRNA-based regulatory circuits operated by iron, nitric oxide and oxidative stress. Proc. Natl. Acad. Sci. USA (1996) 93:8175–8182.
   PubMed Web of Science ®Google Scholar
• RICHARDSON DR: Cytotoxic analogues of the iron(111) chelator pyridoxal isonicotinoyl hydrazone: Effect of complexation with copper(II), gallium(III) and iron(HI) on their anti-proliferative activity. Antimicrob. Agents Chemother. (1997) 41:2061–2063.
   PubMed Web of Science ®Google Scholar
• JOHNSON DK, MURPHY TB, ROSE NJ, GOODWIN WH, PICKART L: Cytotoxic chelators and chelates. 1. Inhibi-tion of DNA synthesis in cultured rodent and human cells by aroylhydrazones and by a copper(ll) complex of salicylaldehyde benzoyl hydrazone. Inorg. Chim. Acta (1982) 67:159–165.
   Google Scholar
• PICKART L, GOODWIN WH, BURGUA W, MURPHY TB,JOHNSON DK: Inhibition of the growth of cultured cells and an implanted fibrosarcoma by aroylhydra-zone analogs of the Gly-His-Lys-Cu(H) complex. Biochem. Pharmacol. (1983) 32:3868–3871.
   PubMed Web of Science ®Google Scholar
• MORAN PL, SELIGMAN PA: Effects of transferrin-indiumon cellular proliferation of a human leukemia cell line. Cancer Res. (1987) 49:4237–4241.
   Web of Science ®Google Scholar
• YUMITA N, SASAKI K, UMERMURA S, NISHIGAKI R: Sonodynamically induced antitumour effect of a gallium-porphyrin complex, ATX-70. Jpn. J. Cancer Res. (1996) 87:310–316.
   PubMedGoogle Scholar
• UMERMURA S, YUMITA N, NISHIGAKI R: Enhancementof ultrasonically induced cell damage by a gallium-porphyrin complex, ATX-70. Jpn. J. Cancer Res. (1993) 84:582–588.
   PubMedGoogle Scholar
• KESSEL D: Porphyrin-lipoprotein association as afactor in porphyrin localisation. Cancer Lea. (1986) 33:183–188.
   PubMed Web of Science ®Google Scholar
• SASAKI K, YUMITA N, NISHIGAKI R, UMEMURA S: Antitumor effect sonodynarnically induced by focused ultrasound in combination with Ga-porphyrin complex. Jpn. J. Cancer Res. (1998) 89:452–456.
   PubMedGoogle Scholar
• WARRELL RP, MURPHY WK, SCHULMAN P, O'DWYER PJ,HELLER G: A randomised double-blind study of gallium nitrate compared with etidronite for acute control of cancer-related hypercalcemia. J. Clin. Oncol. (1991) 9:1467–1475.
   PubMedGoogle Scholar
• WARRELL RP, BOCKMAN RS, COONLEY CJ et al.: Gallium nitrate inhibits calcium resorption from bone and is an effective treatment for cancer-related hypercal-cemia. J. Clin Invest. (1984) 73:1487–1490.
   PubMed Web of Science ®Google Scholar
• BOCKMAN RS, BOSKEY A, BLUMENTHAL NC et al.: Gallium increases bone calcium and crystallite perfec-tion of hydroxyapatite. Calcif Tissue Int. (1986) 39:376–381.
   PubMed Web of Science ®Google Scholar
• ARUFFO AA, MURPHY TB, JOHNSON DK, ROSE NJ, SCHOMAKER V: Structural studies of Fe(HI) and Cu(ll) complexes of salicylaldehyde benzoyl hydrazone, a synthetic chelating agent exhibiting diverse biological properties. Inorg. Chim. Acta (1982) 67125–L27.
   Google Scholar
• RICHARDSON DR, BERNHARDT PV: The crystal and molecular structure of 2-hydroxy-1-naphthaldehyde isonicotinoyl hydrazone (NIH) and its iron(III) complex: an iron chelator with anti-tumour activity. JBIC (1999) 4:266–273.
   PubMed Web of Science ®Google Scholar
• LIU M-C, LIN T-S, SARTORELLI AC: Chemical and biological properties of cytotoxic a-(N)-heterocyclic carboxaldehyde thiosemicarbazones. In: Progress in Medicinal Chemistry, Volume 32. Ellis GP, Luscombe DK (Eds.) Elsevier Science By, UK (1995):1–35.
   Google Scholar
• ••Comprehensive review of the chemical and biologicalproperties of thiosemicarbazones.
   Google Scholar
• MILLER MC III, STINEMAN CN, VANCE JR, WEST DX, HALL IH: Multiple mechanisms for cytotoxicity induced by copper(II) complexes of 2-acetylpyrazine-N-substituted thiosemicarbazones. Appl. Organometal. Chem. (1999) 13:9–19.
   Web of Science ®Google Scholar
• BOOTH B, JOHNS DG, BERTINO JR, SARTORELLI A: Sites of inhibition of DNA synthesis by kethoxal bis (thiosemicarbazone). Nature (1968) 217:250–251.
   PubMed Web of Science ®Google Scholar
• BHUYAN BK, BETZ T: Studies on the mode of action of the copper(II) chelate of 2-keto-3-ethoxy butyraldehyde-bis (thiosemicarbazone). Cancer Res. (1968) 28:758–763.
   PubMed Web of Science ®Google Scholar
• GARCIA-TOJAL J, GARCIA-ORAD A, SERRA JL et al.:Synthesis and spectroscopic properties of copper(H) complexes derived from thiophene-2-carbaldehyde thiosemicarbazone. Structure and biological activity of [Cu(C6H6N352)2]. J. Inorg. Biochem. (1999) 75:45–54.
   Google Scholar
• BYRNES RW, MOHAN M, ANTHOLINE WE, XU RX, PETERING DH: Oxidative stress induced by a copper-thiosemicarbazone complex. Biochemistry (1990) 29:7046–7053.
   PubMed Web of Science ®Google Scholar
• CLARKE MJ: Mutagenicity and modes of metal bindingto nucleic acids. Inorg. Chem. (1980) 19:1103–1104.
   Web of Science ®Google Scholar
• CLARKE MJ, BITLER D, RENNERT D, BUCHBINDER M, KELMAN AD: Reduction and subsequent binding of ruthenium ion catalysed by subcellular components./ Inorg. Biochem. (1980) 12:79–87
   PubMed Web of Science ®Google Scholar
• CLARKE MJ: Oncological implications of the chemistry of ruthenium. In: Metal Ions in Biological Systems, Volume 11. Siegel H (Ed.), Marcel Dekker, New York, USA (1980)231–281.
   Google Scholar
• •Comprehensive review of the chemistry of ruthenium as related to the anticancer properties of ruthenium compounds.
   Google Scholar
• EWALT RX, BENNETT LE: Reactivity characteristics of cytochrome c(lln) adduced from its reduction by hexaammine-ruthenium(ll) ion. J. Am. Chem. Soc. (1974) 96:940–942.
   Web of Science ®Google Scholar
• STANBURY DM, HAAS O, TAUBE H: Reduction of oxygenby ruthenium(II) ammines. Inorg. Chem. (1980) 19:518–524.
   Web of Science ®Google Scholar
• MORGAN EH: Transferrin: biochemistry, physiology and clinical significance. Mol. Aspects. Med. (1981) 4:1–123.
   Web of Science ®Google Scholar
• WEINBERG ED: Iron withholding a defense against infection and neoplasia. Physiol. Rev. (1984) 64:65–102.
   PubMed Web of Science ®Google Scholar
• RICHARDSON DR: Analogues of pyridoxal isonicoti-noyl hydrazone (PM) as potential iron chelators for the treatment of neoplasia. Leuk. Lymphoma (1998) 31:47–60.
   PubMed Web of Science ®Google Scholar
• SOM P, OSTER ZH, MATSUI K et al.: 9711u-transferrin uptake in tumour and abscess. Eur. J. Med. (1983) 8:491–494.
   Google Scholar
• KRATZ F, HARTMANN M, KEPPLER B, MESSORI L: Thebinding properties of two anti-tumour ruthenium(BI) complexes to apotransferrin. J. Biol. Chem. (1994) 269:2581–2588.
   PubMed Web of Science ®Google Scholar
• SMITH CA, SUTHERLAND-SMITH AJ, KEPPLER BK, KRATZF, BAKER EN: Binding of ruthenium(BI) anti-tumor drugs to human lactoferrin probed by high resolution x-ray crystallographic structure analyses. JBIC (1996) 1:424–431.
   Web of Science ®Google Scholar
• SAVA G, BERGAMO A: Drug control of solid tumour metastases: A critical view. AntiCancer Res. (1999) 19:1117-1124. Presents interesting view of the importance of controlling metastasis in cancer treatment.
   Google Scholar
• SAVA G, GAGLIARDI R, BERGAMO A, ALESSIO E, MESTRONI G: Treatment of metastases of solid mouse tumours by NAMI-A: Comparison with cisplatin, cyclophospharnide and dacarbazine. AntiCancer Res. (1999) 19:969–972
   PubMed Web of Science ®Google Scholar
• SAVA G, CLERICI K, CAPOZZI I et al.: Reduction of lung metastasis by imh[trans-RuC14(DMSO)Im]: Mechanism of the selective action investigated on mouse tumors. AntiCancer Drugs. (1999) 10:129–138.
   PubMed Web of Science ®Google Scholar
• BERGAMO A, GAGLIARDI R, SCARCIA V eta/.: In vitro cell cycle arrest, in vivo action on solid metastasizing tumors and host toxicity of the antimetastatic drug NAMI-A and cisplatin. J. Pharmacol. Exp. Ther. (1999) 289:559–564.
   Google Scholar
• CAPOZZI I, CLERICI K, COCCHIETTO M, SALERNO G, BERGAMO A, SAVA G: Modification of cell cycle and viability of TLX5 lymphoma in vitro by sulfoxide-ruthenium compounds and cisplatin detected by flow cytometry. Chem. Biol. Interact. (1998) 113:51–64.
   PubMed Web of Science ®Google Scholar
• SAVA G, CAPOZZI I, CLERICI K, GAGLIARDI G, ALESSIO E,MESTRONI G: Pharmacological control of lung metastases of solid tumours by a novel ruthenium complex. Clin. Exp. Metastasis. (1998) 16:371–379.
   PubMed Web of Science ®Google Scholar
• SAVA G, GAGLIARDI R, COCCHIETTO M et al.: Comparison of the effects of the antimetastatic compound Imh[trans-RuCI4(DMS0)1m] (NAMI-A) on the arthritic rat and on Mca mammary carcinoma in mice. Pathol. Oncol. Res. (1998) 4:30–36.
   PubMedGoogle Scholar
• SAVA G, CAPOZZI I, BERGAMO A et al.: Down-regulation of tumour gelatinase/inhibitor balance and preserva-tion of tumour endothelium by an anti-metastatic ruthenium complex. Int. J. Cancer. (1996) 68:60–66.
   PubMed Web of Science ®Google Scholar
• ••Significant findings on the mechanism of action of this classof Ru complexes.
   Google Scholar
• BERGAMO A, COCCHIETTO M, CAPOZZI I, MESTRONI G,ALESSIO E, SAVA G: Treatment of residual metastases with Na[trans-RuC14 (DMSO)Lm] and ruthenium uptake by tumor cells. AntiCancer Drugs (1996) 6:697–702.
   Google Scholar
• GAGLIARDI R, SAVA G, PACOR S, MESTRONI G, ALESSIOE: Antimetastatic action and toxicity on healthy tissues of Na[trans-RuC14(DMS0)1m] in the mouse. Clin. Exp. Metastasis (1994) 12:93–100.
   PubMed Web of Science ®Google Scholar
• COLUCCIA M, SAVA G, LOSETO F et al.: Anti-leukaemicaction of RuC12 (DMS0)4 isomers and prevention of brain involvement on P388 leukaemia and on P388/DDP sublime. Eur.J. Cancer(1993) 29A:1873–1879.
   PubMed Web of Science ®Google Scholar
• SAVA G, PACOR S, MESTRONI G, ALESSIO E: Na[trans-RuC14(DMS0)1m], a metal complex of ruthenium with antimetastatic properties. Clin. Exp. Metastasis (1992) 10:273–280.
   PubMed Web of Science ®Google Scholar
• SAVA G, PACOR S, BREGANT F, CESCHIA V, MESTRONI G:Metal complexes of ruthenium: Antineoplastic properties and perspectives. AntiCancer Drugs (1990) 1:99–108.
   PubMedGoogle Scholar
• KELLAND LR: Meeting report on 8th international symposium on platinum and other metal coordina-tion compounds in cancer chemotherapy. J. Inorg. Biochem. (1999) 77:121–124.
   PubMed Web of Science ®Google Scholar
• KOPF H, KOPF-MAIER P: Titanocene dichloride - The first metallocene with cancerostatic activity. Angew. Chem. Int. Ed. Engl. (1979) 18:477-478.Landmark paper describing the antitumour potential of TDC.
   Google Scholar
• KOPF-MAIER P: Antitumor activity of titanocene dichlo-ride in xenografted human renal-cell carcinoma. AntiCancer Res. (1999) 19:493–504.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, TORNIEPORTH-OETTING IC: Antitumor activity of titanocene amino acid complexes. Biometals (1996) 9:267–271.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P: Complexes of metals other than platinum as antitumour agents. Eur. J. Clin. Pharmacol. (1994) 47:1–16.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P: Intracellular localization of titanium within xenografted sensitive human tumors after treatment with the antitumor agent titanocene dichlo-ride. J. Struct. Biol. (1990) 105:35–45.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, KLAPOTKE T: Antitumor activity of an ionic titanocene tetrachloroferrate derivative against some solid experimental tumors. Arzneimittelforschung (1989) 39:488–490.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P: Tumor inhibition by titanocene complexes: Influence on xenografted human adenocarcinomas of the gastrointestinal tract. Cancer Chemother. Pharmacol. (1989) 23:225–230.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, NEUSE E, KLAPOTKE T, KOPF H: Ionic titanocene complexes: A new type of antitumor agent. Cancer Chemother. Pharmacol. (1989) 24:23–27.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P: Cytostatic non-platinum metal complexes: New perspectives for the treatment of cancer? Naturwissenschaften (1987) 74:374–382.
   Google Scholar
• KOPF-MAIER P, KOPF H: Tumor inhibition by titano-cene complexes. Activity against B16 melanoma and colon 38 carcinoma. Arzneimittelforschung (1987) 37:532–534.
   Google Scholar
• KOPF-MAIER P: Tumor inhibition by titanocene complexes: Influence upon two xenografted human lung carcinomas. J. Cancer Res. Clin. Oncol. (1987) 113:342–348.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, KOPF H: Antitumor metallocenes: new developments and toxicologic features. AntiCancer Res. (1986) 6:227–233.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, PREISS F, MARX T, KLAPOTKE T, KOPF H: Tumor inhibition by titanocene complexes: Activity against sarcoma 180. Anti Cancer Res. (1986) 6:33–37.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, MOORMANN A, KOPF H: Activity of titanocene dihalides against a human colon carcinoma heterotransplanted to athymic mice. Eur. J. Cancer Clin. Oncol. (1985) 21:853–857.
   PubMedGoogle Scholar
• KOPF-MAIER P, WAGNER W, HESSE B, KOPF H: Tumor inhibition by metallocenes: activity against leukemias and detection of the systemic effect. Eur. J. Cancer (1981) 17:665–669.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, WAGNER W, LISS E: Cytokinetic behaviour of Ehrlich ascites tumor after in vivo treatment with cis-diamminedichloroplatinum(II) and metallocene clichlorides. J. Cancer Res. Clin. Oncol. (1981) 102:21–30.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, KOPF H: Tumor inhibition by titano-cene dichloride: First clues to the mechanism of action. Naturwissenschaften (1980) 67:415–416.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, HESSE B, KOPF H: Tumor inhibition by metallocenes: Effect of titanocene, zirconocene and hafnocene dichlorides on Ehrlich ascites tumor in mice. J. Cancer Res. Clin. Oncol. (1980) 96:43–51.
   PubMed Web of Science ®Google Scholar
• KORFEL A, SCHEULEN ME, SCHMOLL HJ et al.: Phase I clinical and pharrnacokinetic study of titanocene dichloride in adults with advanced solid tumors. Clin. Cancer Res. (1998) 4:2701–2708.
   PubMed Web of Science ®Google Scholar
• LUMMEN G, SPERLING H, LUBOLDT H, OTTO T, RUBBEN H: Phase II trial of titanocene dichloride in advanced renal-cell carcinoma. Cancer Chemother. Pharmacol. (1998) 42:415–417.
   PubMed Web of Science ®Google Scholar
• •The only report of a Phase II trial of TDC.
   Google Scholar
• CHRISTODOULOU CV, FERRY DR, FYFE DW et al.: Phase I trial of weekly scheduling and pharmacokinetics of titanocene dichloride in patients with advanced cancer. J. Clin. Oncol. (1998) 16:2761–2769.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, KOPF H: Organometallic titanium, vanadium, niobium, molybdenum and rhenium complexes - Early transition metal antitumour drugs. In: Metal Compounds in Cancer Therapy. Fricker SP (Ed.) Chapman & Hall, London, UK (1994):109–146.
   Google Scholar
• KOPF-MAIER P, WAGNER W, LISS E: Induction of cell arrest at Gi/S and in G2 after treatment of Ehrlich ascites tumor cells with metallocene dichlorides and cis-platinum in vitro. J. Cancer Res. Clin. Oncol. (1983) 106:44–52.
   PubMed Web of Science ®Google Scholar
• KOPF-MAIER P, KOPF H: Tumour inhibition by metallo-cene dihalides of early transition metals. In: Platinum, Gold and Other Metal Chemotherapeutic Agents. Lippard SJ (Ed.) American Chemical Society, Washington DC, USA (1983):315–333.
   Google Scholar
• MURRAY JH, HARDING MM: Organometallic anticancer agents: The effect of the central metal and halide ligands on the interaction of metallocene dihalides Cp2MX2 with nucleic acid constituents. J. Med. Chem. (1994) 37:1936–1941.
   PubMed Web of Science ®Google Scholar
• CHRISTODOULOU CV, ELIOPOULOS AG, YOUNG LS, HODGKINS L, FERRY DR, KERR DJ: Anti-proliferative activity and mechanism of action of titanocene dichlo-ride. Br. J. Cancer (1998) 77:2088–2097.
   PubMed Web of Science ®Google Scholar
• •Interesting paper adding insight into the mechanism of action of TDC.
   Google Scholar
• HERROD JJ, ELIOPOULOS AG, WARWICK J, NIEDOBITEK G, YOUNG LS, KERR DJ: The prognostic significance of Bc1-2 and p53 expression in ovarian carcinoma. Cancer Res. (1996) 56:2178–2184.
   PubMed Web of Science ®Google Scholar
• DIVE C, HICKMAN JA: Drug-target interactions: only the first step in the commitment to a programmed cell death? Br. J. Cancer (1991) 64:192–196.
   Web of Science ®Google Scholar
• FISHER TC, MILNER AE, GREGORY CD et al.: Bc1-2 modulation of apoptosis induced by anti-cancer drugs: resistance to thymidylate stress is independent of classical resistance pathways. Cancer Res. (1993) 53 :3321–3326.
   PubMed Web of Science ®Google Scholar
• MARTIN SJ, GREEN DR: Apoptosis as a goal of cancer therapy. Curr. opin. Oncol. (1994) 6:616–621.
   PubMedGoogle Scholar
• HARSTRICK A, SCHMOLL HJ, SASS G, POLIWODE H, RUSTUM: Titanocenedichloride activity in cisplatin and doxorubicin-resistant human ovarian carcinoma cell lines. Eur. J. Cancer (1993) 29A:1000–1002.
   PubMed Web of Science ®Google Scholar
• MESSORI L, ORIOLI P, BANHOLZER V, PAIS I, ZATTA P: Formation of titanium(IV) transferrin by reaction of human serum apotransferrin with titanium complexes. FESS Lea. (1999) 442:157–161.
   PubMed Web of Science ®Google Scholar
• FRIEDRICH M, VILLENA-HEINSEN C, FARNHAMMER C, SCHMIDT W: Effects of vinorelbine and titanocene dichloride on human tumour xenografts in nude mice. Eur. J. Gynaecol. Oncol. (1998) 19:333–337.
   PubMed Web of Science ®Google Scholar
• VILLENA-HEINSEN C, FRIEDRICH M, ERTAN AK, FARNHAMMER C, SCHMIDT W: Human ovarian cancer xenografts in nude mice: Chemotherapy trials with paclitaxel, cisplatin, vinorelbine and titanocene dichloride. AntiCancer Drugs (1998) 9:557–563.
   PubMed Web of Science ®Google Scholar
• KELLER HJ, KEPPLER B, SCHMAHL D: Antitumor activity of cis-dihalogenobis(1-phenyl-1,3-butanedionato) titanium(IV) compounds against Walker 256 carcino-sarcoma. A new class of antineoplastic agents. Arzneimittelforschung (1982) 32:806–807.
   Google Scholar
• KEPPLER BK, SCHMAHL D: Preclinical evaluation of dichlorobis(1-phenylbutane-1,3-dionato)titanium (IV) and budotitane. Two representatives of the new class of antitumor-active bis-beta-diketonato metal complexes. Arzneimittelforschung (1986) 36:1822–1828.
   Google Scholar
• FRAHAUF S, ZELLER WJ: New platinum, titanium and ruthenium complexes with different patterns of DNA damage in rat ovarian tumor cells. Cancer Res. (1991) 51:2943–2948.
   PubMed Web of Science ®Google Scholar
• HARTMANN M, KEPPLER BK: Inorganic anti-cancer agents: Their chemistry and anti-tumor properties. Comments Inorg. Chem. (1995) 16:339–372.
   Web of Science ®Google Scholar
• MATTERN J, KEPPLER B, VOLM M: Preclinical evaluation ofdiethoxy-(1-phenyl-1,3-butanedionato)titanium(IV) in human tumour xenografts. Arzneimit-telforschung (1984) 34:1289–1290.
   PubMed Web of Science ®Google Scholar
• SCHILLING T, KEPPLER KB, HEIM ME et al.: ClinicalPhase I and pharrnacokinetic trial of the new titanium complex budotitane. Invest. New Drugs (1996) 13:327–332.
   PubMed Web of Science ®Google Scholar