Emerging DNA topoisomerase inhibitors as anticancer drugs

Expert Opinion on Emerging Drugs

Volumn 9, Issue 1, 2004, Pages 105-133

  Denny, William A ^a  

^a UNIVERSITY OF AUCKLAND   (New Zealand)

Author keywords

Anticancer drugs; Dual topo I II inhibitors; Topo I inhibitors; Topo II inhibitors; Topoisomerase

Indexed keywords

1,4 BIS[[2 (DIMETHYLAMINO N OXIDE)ETHYL]AMINO] 5,8 DIHYDROXYANTHRAQUINONE; 7 ETHYL 10 HYDROXYCAMPTOTHECIN; AMRUBICIN; ANTHRACYCLINE DERIVATIVE; ANTHRAQUINONE DERIVATIVE; ANTINEOPLASTIC AGENT; BELOTECAN; CAMPTOTHECIN; CISPLATIN; CYCLOPHOSPHAMIDE; DIFLOMOTECAN; DNA TOPOISOMERASE; DNA TOPOISOMERASE INHIBITOR; DOXORUBICIN; DX 9851F; ED 0749; EDOTECARIN; EPIRUBICIN; EXATECAN; FLUOROURACIL; GIMATECAN; GYRASE INHIBITOR; IRINOTECAN; KARENITECAN; LACTONE; LU 79553; MITOXANTRONE; MMRDX; N (2 DIMETHYLAMINOETHYL) 9 HYDROXY 5,6 DIMETHYL 6H PYRIDO[4,3 B]CARBAZOLE 1 CARBOXAMIDE; NEMORUBICIN; PIXANTRONE; SABARUBICIN; TAXANE DERIVATIVE; UNCLASSIFIED DRUG; UNINDEXED DRUG; DNA; DNA TOPOISOMERASE (ATP HYDROLYSING); TUMOR PROTEIN;

ANEMIA; ANTINEOPLASTIC ACTIVITY; AREA UNDER THE CURVE; BILIARY EXCRETION; BONE MARROW DEPRESSION; BONE MARROW SUPPRESSION; BREAST CANCER; BREAST CARCINOMA; CANCER CHEMOTHERAPY; CARDIOTOXICITY; CELL TRANSPORT; CHRONIC LYMPHATIC LEUKEMIA; CLINICAL PROTOCOL; CLINICAL TRIAL; COLON ADENOCARCINOMA; CONTINUOUS INFUSION; DNA CLEAVAGE; DOSE RESPONSE; DRUG ACTIVITY; DRUG DESIGN; DRUG EFFICACY; DRUG ELIMINATION; DRUG HALF LIFE; DRUG MECHANISM; DRUG POTENCY; DRUG SOLUBILITY; DRUG STRUCTURE; ESOPHAGUS CANCER; GRANULOCYTOPENIA; HUMAN; IN VITRO STUDY; IN VIVO STUDY; INTERCALATION COMPLEX; LEUKEMIA; LEUKOPENIA; LYMPHOMA; MAXIMUM TOLERATED DOSE; NEUTROPENIA; NONHODGKIN LYMPHOMA; OVARY CANCER; PHASE 1 CLINICAL TRIAL; PHASE 2 CLINICAL TRIAL; QUANTITATIVE STRUCTURE ACTIVITY RELATION; REVIEW; SOFT TISSUE SARCOMA; SOLID TUMOR; STOMACH CANCER; THROMBOCYTOPENIA; TISSUE DISTRIBUTION; ADULT; ANIMAL; CHEMICAL STRUCTURE; CHEMISTRY; CHILD; DRUG ANTAGONISM; DRUG SCREENING; ENZYMOLOGY; METABOLISM; MULTICENTER STUDY; NEOPLASM; STRUCTURE ACTIVITY RELATION;

ADULT; ANIMALS; ANTINEOPLASTIC AGENTS; CHILD; CLINICAL TRIALS; DNA TOPOISOMERASES, TYPE I; DNA TOPOISOMERASES, TYPE II; DNA, NEOPLASM; DRUG DESIGN; DRUG SCREENING ASSAYS, ANTITUMOR; HUMANS; MOLECULAR STRUCTURE; MULTICENTER STUDIES; NEOPLASM PROTEINS; NEOPLASMS; STRUCTURE-ACTIVITY RELATIONSHIP;

EID: 2642517177     PISSN: 14728214     EISSN: None     Source Type: Journal    
DOI: 10.1517/eoed.9.1.105.32948     Document Type: Review

References (242)

1. LIU LF: DNA topoisomerase poisons as antitumor drugs. Ann. Rev. Biochem. (1989) 58:351-375.
2. DENNY WA, BAGULEY BC: Dual topoisomerase I/II inhibitors. Curr. Top. Med. Chem. (2003) 3:339-353.
3. MUGGIA FM, CREAVEN PJ, HANSEN HH, COHEN MH, SELAWRY OS: Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother. Rep. (1972) 56(4):515-521.
4. GOTTLIEB JA, GUARINO AM, CALL JB, OLIVERIO VT, BLOCK JB: Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother. Rep. (1970) 54(6):461-470.
5. JEW S, KIM MG, KIM HJ et al.: Synthesis and in vitro cytotoxicity of C(20)(RS)-camptothecin analogs modified at both B (or A) and E ring. Bioorg. Med. Chem. Lett. (1998) 8(14):1797-1800.
6. AHN SK, CHOI NS, JEONG BS et al.: Practical synthesis of (S)-7-(2-isopropylamino)ethylcamptothecin hydrochloride, potent topoisomerase I inhibitor. J. Het. Chem. (2000) 37(5):1141-1144.
7. LEE JH, LEE JM, KIM JK et al.: Antitumor activity of 7-[2-(N-isopropylamino)ethyl]-(20S)-camptothecin, CKD602, as a potent DNA topoisomerase I inhibitor. Arch. Pharm. Res. (1998) 21(5):581-590. Enzyme inhibition and in vitro cyotoxicity data.
8. LEE JH, LEE JM, LIM KH et al.: Preclinical and Phase I clinical studies with CKD-602, a novel camptothecin derivative. Ann. NY Acad. Sci. (2000) 922:324-325.
9. LEE HS, PARK HJ, LEE JH et al.: Preclinical evaluation of oral CKD-602, a novel camptothecin derivative. Proc. Am. Assoc. Cancer Res. (2003) 44:404 (Abstract 1781).
10. HA KW, OH HY, HEO OS et al.: Genotoxicity studies of an anticancer agent of camptothecin series, CKD-602. Env. Mutagens Carcinogens (1998) 18(2):129-134.
11. KIM HK, BANG YJ, HOE DS, SHIN SG, KIM NK: Phase I trial of CKD-602, a novel camptothecin derivative, in patients with advanced solid tumors. Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 393).
12. CHO JY, SEO HB, YU KS et al.: Simple and sensitive determination of the new antitumor drug CDK-602 in human plasma by liquid chromatography. J. Chromat. B-Anal. Technol. Biomed. Life Sci. (2003) 784(1):25-31.
13. SONG Y, SEO SS, BANG YJ et al.: Phase II evaluation of CDK-602, a camptothecin analog, administered on a 5-day schedule in patients with recurrent or refractory ovarian cancer. Proc. Am. Soc. Clin. Oncol. (2003) 22:467 (Abstract 1877).
14. BOM D, CURRAN DP, CHAVAN AJ et al.: Novel A,B,E-ring modified camptothecins displaying high lipophilicity and markedly improved human blood stabilities. J. Med. Chem. (1999) 42(16):3018-3022.
15. KUMAZAWA E, TOHGO A: Antitumor activity of DX-8951f: a new camptothecin derivative. Expert Opin. Investig. Drugs (1998) 7(4):625-632.
16. KUMAZAWA E, JIMBO T, OCHI Y, TOHGO A: Potent and broad antitumor effects of DX-8951f, a water-soluble camptothecin derivative, against various human tumors xenografted in nude mice. Cancer Chemother. Pharmacol. (1998) 42(3):210-220. Evidence of in vivo activity in Pgp-overexpressing cell lines.
17. JOTO N, ISHII M, MINAMI M, KUGA H, MITSUI I, TOHGO A: DX-8951f, a water-soluble camptothecin analog, exhibits potent antitumor activity against a human lung cancer cell line and its SN-38-resistant variant. Int. J. Cancer (1997) 72(4):680-686.
18. NOMOTO T, NISHIO K, ISHIDA T, MORI M, SAIJO N: Characterization of a human small-cell lung cancer cell line resistant to a new water-soluble camptothecin derivative, DX-8951f. Jpn. J. Cancer Res. (1998) 89(11):1179-1186.
19. MINAMI H, SASAKI Y, SHIGEOKA Y et al.: Phase I study and pharmacology of DX-8951f, a new camptothecin derivative, administered over 30 minutes every 3 weeks. AACR-NCI-EORTC Molecular Targets and Cancer Therapeutics, Washington DC, USA (1999) (Abstract 326).
20. ROWINSKY E, JOHNSON T, GEYER C et al.: DX-8951f, a hexacyclic camptothecin analog on a daily x 5 schedule: a Phase I and pharmacokinetic study in patients with advanced solid malignancies. J. Clin. Oncol. (2000) 18(17):3151-3163. Full Phase I clinical trial report.
21. ROYCE M, LASSERE Y, HOFF P et al.: DX-8951f: Phase I and pharmacokinetic study of a novel camptothecin analog admnistered by 24-hr continuous infusion to patients with advanced solid tumors. Proc. Am. Soc. Clin. Oncol. (1999) 18 (Abstract 682).
22. GARRISON M, HAMMOND LA, GEYER C et al.: A Phase I and pharmacokinetic study of the camptothecin (CPT) analog DX-8951F (exatecan mesylate): escalating infusion duration and dose. Proc. Am. Soc. Clin. Oncol. (2000) 19 (Abstract 765).
23. PATT YZ, ROWINSKY E, O'REILLY E et al.: Phase II trial of DX-8951f (Exatecan Mesylate) In hepatocellular carcinoma (HCC); a final analysis. Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 555).
24. ESTEVA FJ, RIVERA E, CRISTOFANILLI M et al.: A Phase II study of intravenous exatecan mesylate (DX-8951f) administered daily for five days every three weeks to patients with metastatic breast cancer. Proc. Am. Soc. Clin. Oncol. (2003) 22:17 (Abstract 67).
25. ABOU-ALFA GK, O'REILLY EM, ROWINSKY EK et al.: Final results of a Phase II study of DX-8951f (DX, Exatecan Mesylate) in biliary tree cancers. Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 561).
26. KUDELKA A, VERCHRAEGEN CF, VINCENT M et al.: Phase II study of intravenous DX-8951f in patients with advanced ovarian, tubal, or peritoneal cancer refractory to platinum, Taxane, and Topotecan. Proc. Am. Soc. Clin. Oncol. (2000) 19 (Abstract 1550).
27. TALBOT DC, WHITE S, JONES P et al.: Phase II study of exatecan mesylate (DX-8951f) in advanced NSCLC. Proc. Am. Soc. Clin. Oncol. (2000) 19 (Abstract 2166).
28. ROYCE M, SALTZ L, ROWINSKY EK et al.: A Phase II study of intravenous exatecan mesylate (Dx-8951f,Dx) administered daily for five days every three weeks to patients with advanced or metastatic adenocarcinoma of the colon or rectum. Proc. Am. Soc. Clin. Oncol. (2000) 19 (Abstract 1129).
29. D'ADAMO D, HAMMOND L, DONEHOWER R et al.: Final results of a Phase II study of DX-8951f (Exatecan Mesylate, DX) in advanced pancreatic cancer. Proc. Am. Soc. Clin. Oncol. (2001) 20 (Abstract 532).
30. DALLAVALLE S, FERRARI A, BIASOTTI B, MERLINI L, ZUNINO F: Novel 7-oxyiminomethyl derivatives of camptothecin with potent in vitro and in vivo antitumor activity. J. Med. Chem. (2001) 44(20):3264-3274. Extensive SAR studies showing correlation of enzyme inhibition and in vitro cytotoxicity with lipophilicity.
31. DALLAVALLE S, FERRARI A, MERLINI L et al.: Novel cytotoxic 7-iminomethyl and 7-aminomethyl derivatives of camptothecin. Bioorg. Med. Chem. Lett. (2001) 11(3):291-294.
32. DI FRANCESCO A, MECO D, PISANO C et al.: Antitumour activity of the novel 7-substituted camptothecin ST1481 (Gimatecan) against the human neuroblastoma SN-K-DZ. Proc. Am. Assoc. Cancer Res. (2003) 44:811 (Abstract 3551).
33. ZANNA C, CALABRESI P, CORSI M et al.: Potent and less schedule-dependent antitumor activity of the oral camptothecin derivative ST 1481. Proc. Am. Soc. Clin. Oncol. (2001) 20 (Abstract 406).
34. ALDERSON L, SUPKO J, MAESTRI X et al.: Phase I/II trial of gimatecan in patients with recurrent malignant glioma. Proc. Am. Soc. Clin. Oncol. (2003) 22:104 (Abstract 416).
35. ZHU AX, READY NE, CLARK JW et al.: Phase I trial of gimatecan given orally once a week for 3 of 4 weeks in patients with advanced solid tumors. Proc. Am. Soc. Clin. Oncol. (2003) 22:139 (Abstract 557).
36. SESSA C, HESS D, BASELGA J et al.: Concerted escalation of dose and dosing-duration in a Phase I study of the oral camptothecin Gimatecan (ST 1481) in patients with advanced solid tumors. Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 386).
37. ZUCCHETTI M, PACE S, FRAPOLLI R et al.: Clinical pharmacokinetic profile of Gimatecan (ST 1481), a new oral campthotecin derivative. Proc. Am. Soc. Clin. Onco. (2002) 21 (Abstract 476).
38. VAN HATTUM AH, PINEDO HM, SCHLUPER HMM, HAUSHEER FH, BOVEN E: New highly lipophilic captothecin BNP1350 is an effective drug in experimental human cancer. Int. J. Cancer (2000) 88(2):260-266.
39. VAN HATTUM AH, SCHLUPER HM, HAUSHEER FH, PINEDO HM, BOVEN E: Novel camptothecin derivative BNP1350 in experimental human ovarian cancer: determination of efficacy and possible mechanisms of resistance. Int. J. Cancer (2002) 100(1):22-29.
40. KEIR ST, HAUSHEER F, LAWLESS AA, BIGNER DD, FRIEDMAN HS: Therapeutic activity of 7-[(2-trimethylsilyl)ethyl)]-20 (S)-camptothecin against central nervous system tumor-derived xenografts in athymic mice. Cancer Chemother. Pharmacol. (2001) 48(1):83-87. Demonstration of in vivo activity in CNS tumours.
41. YIN MING B, HAPKE G, WU J, AZRAK R, FRANK C, WRZOSEK C, RUSTUM YM: Chk1 signaling pathways that mediated G(2)M checkpoint in relation to the cellular resistance to the novel topoisomerase I poison BNP1350. Biochem. Biophys. Res. Comm. (2002) 295(2):435-444.
42. SCHILSKY RL, HAUSHEER FH, BERTUCCI D, BERGHORN EJ, KINDLER HL, RATAIN MJ: Phase I trial of karenitecin (KT) administered intravenously daily for five consecutive days in patients with advanced solid tumors using accelerated dose titration. Proc. Am. Soc. Clin. Oncol. (2000) 19 (Abstract 758).
43. THOMPSON P, BERG S, GURURANGAN S et al.: A Phase I study of karenitecin in children. Proc. Am. Assoc. Cancer Res. (2002) 43:553 (Abstract 2748).
44. HERNDON JE, MILLER AA, ZHANG C, GREEN MR: Phase II trial of karenitecin in patients with refractory non-small cell lung cancer (NSCLC): CALGB 30004. Proc. Am. Soc. Clin. Oncol. (2003) 22:673 (Abstract 2706).
45. DAUD A, BALAR B, VALKOV N et al.: Phase II trial of karenitecin, a novel topoisomerase I inhibitor in metastatic melanoma: clinical and translational study. Proc. Am. Soc. Clin. Oncol. (2003) 22:714 (Abstract 2871).
46. LAVERGNE O, DEMARQUAY D, BAILLY C et al.: Topoisomerase I-mediated antiproliferative activity of enantiomerically pure fluorinated homocamptothecins. J. Med. Chem. (2000) 43(11):2285-2289. Extensive SAR studies with homocamptothecin analogues.
47. LAVERGNE O, LESUEUR GL, PLA RF, BIGG DCH: BN-80245: an E-ring modified camptothecin with potent antiproliferative and topoisomerase I inhibitory activities. Bioorg. Med. Chem. Lett. (1997) 7(17):2235-2238.
48. LESUEUR GL, DEMARQUAY D, KISS R, KASPRYZK PG, LAVERGNE O: Homocamptothecin, an E-ring modified camptothecin with enhanced lactone stability, retains topoisomerase I-targeted activity and antitumor properties. Cancer Res. (1999) 59(12):2939-2943. Detailed studies with diflomtecan.
49. LAVERGNE O, GINOT L, RODAS F et al.: Homocamptothecins: synthesis and antitumor activity of novel E-ring-modified camptothecin analogues. J. Med. Chem. (1998) 41(27):5410-5419.
50. GABARDA AE, DU W, ISARNO T et al.: Asymmetric total synthesis of (20R)-homocamptothecin, substituted homocamptothecins and homosilatecans. Tetrahedron (2002) 58(32):6329-6341.
51. LAVERGNE O, DEMARQUAY D, KASPRZYK PG, BIGG DC: Homocamptothecins: E-ring modified CPT analogues. Ann. NY Acad. Sci. (2000) 922:100-111.
52. DEMARQUAY D, HUCHET M, COULOMB H et al.: The homocamptothecin BN 80915 is a highly potent orally active topoisomerase I poison. Anticancer Drugs (2001) 12(1):9-19.
53. BAILLY C, LANSIAUX A, DASSONNEVILLE L et al.: Homocamptothecin, an E-ring-modified camptothecin analogue, generates new topoisomerase I-mediated DNA breaks. Biochemistry (1999) 38(47):15556-15563.
54. PHILIPPART P, HARPER L, CHABOTEAUX C et al.: Homocamptothecin, an E-ring-modified camptothecin, exerts more potent antiproliferative activity than other topoisomerase I inhibitors in human colon cancers obtained from surgery and maintained in vitro under histotypical culture conditions. Clin. Cancer Res. (2000) 6(4):1557-1562. Comparison with other topo I inhibitors in early passage human tumour lines.
55. BATES S, PEREZ WM, KOHLHAGEN G, POMMIER YG: BRCP/MXR/ABCG2-mediated resistance to homocamptothecins. Proc. Am. Assoc. Cancer Res. (2003) 44:137 (Abstract 595).
56. SOLA J, GAY-FEUTRY C, MASSIERE F, PERAIRE C, OBACH R, PRINCIPE P: In vitro metabolism of diflomotecan in humans. Evaluation of the CYP inhibition potential. Drug Met. Rev. (2003) 35(Suppl. 1).
57. BONNETERRE J, COTTU P, ADENIS A, BONETERRE ME et al.: First results of Phase I trial of BN-80915 administered intravenousley in patients with advanced malignant tumors. NCI-EORTC Symposium New Drug for Cancer Therapy (2000) 11 (Abstract 234).
58. SOEPENBERG O, SCOTT L, VERWIEJ J, DAMJI R et al.: Phase I and pharmacologic study of diflomotecan (BN80915) administered intravenously daily for 5 consecutive days every 3 weeks in patients with solid tumors. 14th EORTC-NCI-AACR Symposium of Molecular Targets and Cancer Therapeutics, Frankfurt, Germany (2002) (Abstract 139).
59. SALAZAR R, GELDERBLOM AJ, TWELVES CJ, DEJONGE M et al.: A Phase I bioavailability and dose finding study of BN80915 administered orally to patients with advanced malignant tumors. Proc. Am. Soc. Clin. Oncol. (2001) 20 (Abstract 418).
60. OHKUBO M, NISHIMURA T, HONMA T et al.: Synthesis and biological activities of NB-506 analogues: effects of the positions of two hydroxyl groups at the indole rings. Bioorg. Med. Chem. Lett. (1999) 9:3307-3312.
61. AKAO A, HIRAGA S, IIDA T et al.: Practical synthesis of a potent indolocarbazole-based, DNA topoisomerase inhibitor. Tetrahedron (2001) 57(43):8917-8923.
62. YOSHINARI T, OHKUBO M, FUKASAWA K, EGASHIRA SI, HARA Y: Mode of action of a new indolocarbazole anticancer agent, J-107088, targeting topoisomerase I. Cancer Res. (1999) 59(17):4271-4275.
63. KOMATANI H, KOTANI H, HARA Y et al.: Identification of breast cancer resistant protein/mitoxantrone resistance/placenta-specific, ATP-binding cassette transporter as a transporter of NB-506 and J-107088 topoisomerase I inhibitors with an indolocarbazole structure. Cancer Res. (2001) 61(7):2827-2832. Nice study of efflux mechanisms for edotecarin.
64. GOOSSENS JF, KLUZA J, VEZIN H et al.: Plasma stability of two glycosyl indolocarbazole antitumor agents. Biochem. Pharmacol. (2003) 65(1):25-34.
65. TAKENAGA N, ISHII M, KAMEI T, YASUMORI T: Structure-activity relationship in O-glucuronidation of indolocarbazole analogs. Drug Met. Disp. (2002) 30(5):494-497.
66. ARAKAWA H, MORITA M, KODERA T et al.: In vivo anti-tumor activity of a novel indolocarbazole compound, J-107088, on murine and human tumors transplanted into mice Jpn. J. Cancer Res. (1999) 90(10):1163-1170.
67. PECK RA: Phase I trial of J-107088, a novel topoisomerase I inhibitor, administered once every 21 days. Proc. Am. Soc. Clin. Oncol. (2000) 19 (Abstract 767).
68. YAMADA Y, YAMAMOTO N, SHIMOYAMA T et al.: Phase I trial of J-107088, a novel topoisomerase I inhibitor, administered once every 21 days. Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 385).
69. PEREZ RP, HURWITZ H, NAHUM K et al.: Phase II trials of J-107088, a non-camptothecin topoisomerase I inhibitor, in irinotecan naïve/refractory metastatic colorectal cancer. Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 632).
70. NAHUM K, SHIBA D, PADAVANIJA P et al.: Phase II efficacy and tolerability study of edotecarin (J-107088) in patients with irinotecan-naïve metastatic colorectal cancer (MCRC). Proc. Am. Soc. Clin. Oncol. (2003) 22:274 (Abstract 1099).
71. QUINTIERI L, ROSATO A, NAPOLI E et al.: In vivo antitumor activity and host toxicity of methoxymorpholinyl doxorubicin: role of cytochrome P450 3A. Cancer Res. (2000) 60(12):3232-3238. Studies of the liver metabolism of nemorubicin.
72. BEULZ-RICHE D, ROBERT J, MENARD C, RATANASAVANH D: Metabolism of methoxymorpholinodoxorubicin in rat, dog and monkey liver microsomes: comparison with human microsomes. Fund. Clin. Pharmacol. (2001) 15(6):373-378
73. GRANDI M, BALLINARI D, CAPOLONGO L et al.: A new anthracycline and multidrug resistance. Haematologica (1991) 76(Suppl. 3):181-183.
74. RIPAMONTI M, PEZZONI G, PESENTI E et al.: In vivo anti-tumour activity of FCE 23762, a memoxymorpholinyl derivative of doxorubicin active on doxorubicin-resistant tumour cells. Br. J. Cancer (1992) 65(5):703-707.
75. GRANDI M, PEZZONI G, BALLINARI D et al.: Novel anthracycline analogs. Cancer Treat. Rev. (1990) 17(2-3):133-138.
76. BREDA M, BENEDETTI MS, BATTAGLIA R et al.: Species-differences in disposition and reductive metabolism of methoxymorpholinodoxorubicin (PNU 152243), a new potential anticancer agent. Pharmacol. Res. (2000) 41(2):239-248.
77. VASEY PA, BISSETT D, STROLIN-BENEDETTI M et al.: Phase I clinical and pharmacokinetic study of 3′-deamino-3′ -(2-methoxy-4-morpholinyl)doxorubicin (FCE 23762). Cancer Res. (1995) 55(10):2090-2096.
78. FOKKEMA E, VERWEIJ J, VAN OOSTEROM AT: A prolonged methoxymorpholino doxorubicin (PNU-152243 or MMRDX) infusion schedule in patients with solid tumors: a Phase I and pharmacokinetic study. Br. J. Cancer (2000) 82(4):767-771. Full Phase I clinical trial report on nemorubicin.
79. GRAUL A, LEESON PA, CASTANER J: Nemorubicin: antineoplastic anthracycline; Drugs Future (1997) 22(12):1319-1324.
80. SUN Y, LI H, LIN Z et al.: Phase I and pharmacokinetic study of nemorubicin hydrochloride (methoxymorpholino doxorubicin; PNU-152243) administered with iodinated oil via hepatic artery (IHA) to patients (pt) with unresectable hepatocellular carcinoma (HCC). Proc. Am. Soc. Clin. Oncol. (2003) 22:361 (Abstract 1448).
81. UDEA T, FUKUSHIMA T: Recent developments with novel anthracyclines for the treatment of haematological malignancies. Expert Opin. Investig. Drugs (1996) 5(12):1639-1646.
82. YAMAOKA T, HANADA M, ICHII S, MORISADA S, NOGUCHI T, YANAGI Y: Cytotoxicity of amrubicin, a novel 9-aminoanthracycline, and its active metabolite amrubicinol on human tumor cells. Jpn. J. Cancer Res. (1998) 89(10):1067-1073. Metabolism and cytotoxicity studies on amrubicin.
83. OHMORI H, TSUSHIMA T, KOBASHI K: Experimental studies on intravesical instillation of SM-5887, a novel anthracycline derivative for treatment of bladder carcinoma. Gan To Kagaku Ryoho (1996) 23(5):601-606.
84. HANADA M, NOGUCHI T, MURAYAMA T: Profile of the anti-tumor effects of amrubicin, a completely synthetic anthracycline. Nippon Yakurigaku Zasshi (2003) 122(2):141-150.
85. HANADA M, MIZUNO S, FUKUSHIMA A, SAITO Y, NOGUCHI T, YAMAOKA T: A new antitumor agent amrubicin induces cell growth inhibition by stabilizing topoisomerase II-DNA complex. Jpn. J. Cancer Res. (1998) 89(11):1229-1238.
86. OHE Y, NAKAGAWA K, FUJIWARA Y et al.: In vitro evaluation of the new anticancer agents KT6149, MX-2, SM5887, menogaril, and liblomycin using cisplatin- or adriamycin-resistant human cancer cell lines. Cancer Res. (1989) 49(15):4098-4102.
87. MORISADA S, YANAGI Y, NOGUCHI T, KASHIWAZAKI Y, FUKUI M: Antitumor activities of a novel 9-aminoanthracycline (SM-5887) against mouse experimental tumors and human tumor xenografts. Jpn. J. Cancer Res. (1989) 80(1):69-76.
88. YAMAUCHI S, KUDOH S, KIMURA T, HIRATA K, YOSHIKAWA J: Additive effects of amrubicin with cisplatin on human lung cancer cell lines. Osaka City Med. J. (2002) 48(1):69-76.
89. NOGUCHI T, ICHII S, MORISADA S, YAMAOKA T, YANAGI Y: In vivo efficacy and tumor-selective metabolism of amrubicin to its active metabolite. Jap. J. Cancer Res. (1998) 89(10):1055-1060. Nice correlation between rates of metabolism of amrubicin to the 13-alcohol and activity in human xenografts.
90. TSUJIMOTO S, SATOH E, SUGIMOTO SI et al.: General pharmacological studies of a novel anthracycline derivative, (7S, 9S)-9-acetyl-9-amino-7-[(2-deoxy-beta-D-erythro-pentopyranosyl)oxy]-7,8,9, 10-tetrahydro-6,11-dihydroxy-5, 12-naphthacenedione hydrochloride (SM-5887), with antitumor activity. Pharmacometrics (1996) 52(5):351-370.
91. INOUE K, OGAWA M, HORIKOSHI N et al.: Phase I study of SM-5887, a new anthracycline derivative. Gan To Kagaku Ryoho (1988) 15(5):1771-1776.
92. TSUSHIMA T, OHMORI H: A Phase II study of amrubicin (SM-5887), a novel 9-aminoanthracycline, in patients with superficial bladder cancer: a randomized study of intravesical chemotherapy comparing 6 consecutive day and thre consecutive day-4 day interval treatment schedules. Can. J. Infect. Dis. (1995) 6(Suppl. C).
93. YANA T, NEGORO S, TAKADA Y, YOKOTA S, FUKUOKA M: Phase II study of amrubicin (SM-5887), a 9-amino-anthracycline, in previously untreated patients with extensive stage small-cell lung cancer (ES-SCLC): a West Japan Lung Cancer Group trial. Proc. Am. Soc. Clin. Oncol. (1998) 17 (Abstract 1734).
94. TEMPERINI C, MESSORI L, ORIOLI P, DI BUGNO C, ANIMATI F, UGHETTO G: The crystal structure of the complex between a disaccharide anthracycline and the DNA hexamer d(CGATCG) reveals two different binding sites involving two DNA duplexes. Nucleic Acids Res. (2003) 31(5):1464-1469.
95. BIGIONI M, SALVATORE C, BULLO A et al.: A comparative study of cellular and molecular pharmacology of doxorubicin and MEN 10755, a disaccharide analogue. Biochem. Pharmacol. (2001) 62(1):63-70. Study analysing the relationship between rates of uptake and cardiotoxicity for MEN-10755 and doxorubicin.
96. ARCAMONE F, ANIMATI F, BERETTONI M et al.: Doxorubicin disaccharide analogue: apoptosis-related improvement of efficacy in vivo. J. Natl. Cancer Inst. (1997) 89(16):1217-1223.
97. SACCO G, GIAMPIETRO R, SALVATORELLI E et al.: Chronic cardiotoxicity of anticancer anthracyclines in the rat: role of secondary metabolites and reduced toxicity by a novel anthracycline with impaired metabolite formation and reactivity. Br. J. Pharmacol. (2003) 139(3):641-651. In vivo studies correlating the cardiotoxicity of MEN-10775 and other anthracyclines with myocardial levels of the alcohol metabolites.
98. MINTTI G, LICATA S, SAPONIERO A et al.: Anthracycline metabolism and toxicity in human myocardium: comparisons between doxorubicin, epirubicin, and a novel disaccharide analog with a reduced level of formation and [4Fe-4S] reactivity of its secondary alcohol metabolite. Chem. Res. Tox. (2000) 13(12):1336-1341.
99. BOS AM, DEVRIES EG, DOMBERNOVSKY P et al.: Pharmacokinetics of MEN-10755, a novel anthracycline disaccharide analogue, in two Phase I studies in adults with advanced solid tumours. Cancer Chemother. Pharmacol. (2001) 48(5):361-369.
100. PRATESI G, DECESARE M, CASERINI C et al.: Improved efficacy and enlarged spectrum of activity of a novel anthracycline disaccharide analogue of doxombicin against human tumor xenografts. Clin. Cancer Res. (1998) 4(11):2833-2839.
101. CAMARDA G, BINASCHI M, MAGGI CA, GOSO C: Nuclear factor-κB, induced in human carcinoma cell line A2780 by the new anthracycline MEN 10755, is devoid of transcriptional activity. Int. J. Cancer (2002) 102(5):476-482.
102. CIRILLO R, SACCO G, VENTURELLA S, BRIGHTWELL J, GIACHETTI A, MANZINI S: Comparison of doxorubicin- and MEN 10755-induced long-term progressive cardiotoxicity in the rat. J. Cardiovasc. Pharmacol. (2000) 35(1):100-108.
103. ZUCCHI R, YU G, GHELARDONI S, RONCA F, RONCA-TESTONI S: Effect of MEN 10755, a new disaccharide analogue of doxorubicin, on sarcoplasmic reticulum Ca(2+) handling and contractile function in rat heart. Br. J. Pharmacol. (2000) 131(2):342-348.
104. MINOTTI G, PARLANI M, SALVATORELLI E et al.: Impairment of myocardial contractility by anticancer anthracyclines: role of secondary alcohol metabolites and evidence of reduced toxicity by a novel disaccharide analogue. Br. J. Pharmacol. (2001) 134(6):1271-1278.
105. SCHRIJVERS D, BOS A, DYCK J et al.: Phase I study of MEN-10755, a new anthracycline in patients with solid tumours: a report from the EORTC Early Clinical Studies Group. Ann. Oncol. (2002) 13(3):385-391.
106. DICKGREBER NJ, WELTE T, GILLISSEN A et al.: Phase II open-label study of MEN-10755 in patients with small cell lung cancer extensive disease (SCLC-ED). Proc. Am. Soc. Clin. Oncol. (2003) 22:703 (Abstract 2829).
107. CAPONIGRO F, WILLEMSE P, SORIO R et al.: A Phase II study of MEN-10755 in patients with advanced or metastatic ovarian cancer. 14th EORTC-NCI-AACR Symposium of Molecular Targets and Cancer Therapeutics, Frankfurt, Germany (2002) (Abstract 42).
108. KRAPCHO AP, PETRY ME, GETAHUN Z et al.: 6,9-bis[(aminoalkyl)amino]benzo[g]isoquinolin e-5,10-diones. A novel class of chromophore modified antitumour anthracene-9,10-diones; synthesis and antitumour evaluations. J. Med. Chem. (1994) 37(6):828-837.
109. BEGGIOLIN G, CRIPPA L, MENTA E et al.: BBR 2778, an aza-anthracenedione endowed with preclinical anticancer activity and lack of delayed cardiotoxicity. Tumori (2001) 87(6):407-416. Compound selection based on in vivo activity and low cardiotoxicity.
110. ANDOH T, ISHIDA R: Catalytic inhibitors of DNA topoisomerase II. Biochim. Biophys. Acta Gene Struct. Expr. (1998) 1400(1-3):155-171.
111. DE ISABELLA P, PALUMBO M, SISSI C et al.: Topoisomerase II DNA cleavage stimulation, DNA binding activity, cytotoxicity, and physico-chemical properties of 2-aza- and 2-aza-oxide-anthracenedione derivatives. Mol. Pharmacol. (1995) 48(1):30-38.
112. ZWELLING LA, MAYES J, ALTSCHULER E, SATITPUNWAYCHA P, TRITTON TR, HACKER MP: Activity of two novel anthracene-9, 10-diones against human leukemia cells containing intercalator-sensitive or -resistant forms of topoisomerase II. Biochem. Pharmacol. (1993) 46(2):265-271.
113. CAVALLETTI E, CRIPPA L, MELLONI E, BELLINI O, TOGNELLA S, GIULINI FC: BBR 2778, a novel aza-anthracenedione: preclinical toxicological evaluation. Proc. Am. Assoc. Cancer Res. (1993) 34:374 (Abstract 2227).
114. BERNAREGGI A, TORTI L, RATTI E et al.: Clinical pharmacokinetics of BBR-2778 in patients with malignant lymphoma. Proc. Am. Soc. Clin. Oncol. (1999) 18 (Abstract 730).
115. DAWSON LK, JODRELL DI, BOWMAN A et al.: A clinical Phase I and pharmacokinetic study of BBR 2778, a novel anthracenedione analogue, administered intravenously, 3 weekly. Eur. J. Cancer (2000) 36(18):2353-2359.
116. FAIVRE S, RAYMOND E BOIGE V et al.: A Phase I and pharmacokinetic study of the novel aza-anthracenedione compound BBR 2778 in patients with advanced solid malignancies. Clin. J. Cancer Res. (2001) 7(1):43-50.
117. BORCHMANN P, SCHNELL R, KNIPPERTZ R et al.: Phase I study of BBR 2778, a new aza-anthracenedione, in advanced or refractory non-Hodgkin's lymphoma. Ann. Oncol. (2001) 12(5):661-667.
118. BORCHMANN P, MORSCHHAUSER F, PARRY A et al.: Phase-II study of the new aza-anthracenedione, BBR 2778, in patients with relapsed aggressive non-Hodgkin's lymphomas. Haematologica (2003) 88(8):888-894. Full report of Phase II clinical trial.
119. RALEIGH SM, WANOGHO E, BURKE MD, MCKEOWN SR, PATTERSON LH: Involvement of human cytochromes P450 (CYP) in the reductive metabolism of AQ4N, a hypoxia activated anthraquinone di-N-oxide prodrug. Int. J. Radiat. Oncol. Biol. Phys. (1998) 42(4):763-767.
120. WILSON WR, DENNY WA, PULLEN SM et al.: Tertiary amine N-oxides as bioreductive drugs: DACA N-oxide, nitracrine N-oxide and AQ4N. Br. J. Cancer (1996) 74(Suppl. 27):43-47.
121. SMITH PJ, BLUNT NJ, DESNOYERS R, GILES Y, PATTERSON LH: DNA topoisomerase II-dependent cytotoxicity of alkylaminoanthraquinones and their N-oxides. Cancer Chemother. Pharmacol. (1997) 239(5):455-461.
122. HEJMADI MV, MCKEOWN SR, FRIERY OP, MCINTYRE IA, PATTERSON LH, HIRST DG: DNA damage following combination of radiation with the bioreductive drug AQ4N: possible selective toxicity to oxic and hypoxic tumour cells. Br. J. Cancer (1996) 73(4):499-505.
123. FRIERY OP, GALLAGHER R, MURRAY MM et al.: Enhancement of the anti-tumour effect of cyclophosphamide by the bioreductive drugs AQ4N and tirapazamine. Br. J. Cancer (2000) 82(8):1469-1473.
124. PATTERSON LH, MCKEOWN SR, RUPARELIA K et al.: Enhancement of chemotherapy and radiotherapy of murine tumors by AQ4N, a bioreductively activated anti-tumor agent. Br. J. Cancer (2000) 82(12):1984-1990. Combination studies of AQ4N and radio- or chemotherapy in vivo.
125. LOADMAN PM, SWAINE DJ, BIBBY MC, WELHAM KJ, PATTERSON LH: A preclinical pharmacokinetic study of the bioreductive drug AQ4N. Drug Metab. Dispos. (2001) 29(4):422-426.
126. JASZTOLD-HOWORKO R, LANDRAS C, PIERRE A et al.: Synthesis and evaluation of 9-hydroxy-5-methyl-(and 5,6-dimethyl)6H-pyrido[4,3-b]carbazole-1-N-[(dialkylamino)-alkyl]carboxamides, a new promising series of antitumor olivacine derivatives. J. Med. Chem. (1994) 37(15):2445-2452.
127. LE MEES PA, MARKOVITS J, ATASSI G, JACQUEMIN-SABLON A, SAUCIER JM: S16020-2, a new highly cytotoxic antitumor olivacine derivative: DNA interaction and DNA topoisomerase II inhibition. Mol. Pharmacol. (1998) 53(2):213-220.
128. PIERRE A, LEONCE S, PEREZ V, ATASSI G: Circumvention of P-glycoprotein-mediated multidrug resistance by S16020-2: Kinetics of uptake and efflux in sensitive and resistant cell lines. Cancer Chemother. Pharmacol. (1998) 42(6):454-460. Studies of the mechanism of resistance to MDR by S-16020-2.
129. GUILBAUD N, KRAUS-BERTHIER L, SAINT DIZIER D: In vivo antitumor activity of S16020-2, a new olivacine derivative. Cancer Chemother. Pharmacol. (1996) 38(6):513-521.
130. LE ME, S, CHAMINADE F, DELAPORTE C et al.: Cellular resistance to the antitumor DNA topoisomerase II inhibitor S16020-2: importance of the N-[2(dimethylamino)ethyl]carbamoyl side chain. Mol. Pharmacol. (2000) 58(4):709-718.
131. GUILBAUD N, JAN M, SAINT DIZIER D et al.: Experimental antitumour activity of S 16020-2 in a panel of human tumours. Eur. J. Cancer (1997) 33(11):1881-1887. Extensive study of the in vivo activity of S16020-2 in human tumour xenografts.
132. GUILBAUD N, KRAUS-BERTHIER L, SAINT-DIZIER D et al.: Antitumor activity of S 16020-2 in two orthotopic models of lung cancer. Anticancer Drugs (1997) 8(3):276-282.
133. BRILLANCEAU MH, LUCAS C, BRIGGS M, GORDON B, GENISSEL P: Pharmacokinetics and metabolism of the olivacine S-16020 in cancer patients. Proc. Am. Assoc. Cancer Res. (1998) 39:327 (Abstract 2229).
134. DIPALMA M, BRAIN EC, ETOUSSAMI A et al.: Phase I study of olivacine (S16020) in a weekly schedule: Preliminary results. Proc. Am. Assoc. Cancer Res. (1999) 40:83 (Abstract 555).
135. AWADA A, BLEIBERG H, GIL T et al.: Phase I study of S16020, a topoisomerase II inhibitor given q 3 w as a 3-h infusion. Proc. Am. Assoc. Cancer Res. (1999) 40:83 (Abstract 4501).
136. BRANA MF, CASTELLANO JM, MORAN M et al.: Bis-naphthalimides 3: synthesis and antitumor activity of N,N′-bis[2-(1,8-naphthalimido)-ethyl] alkanediamines. AntiCancer Drug Des. (1996) 11(4):297-309.
137. SPICER JA, GAMAGE SA, ATWELL GJ, FINLAY GJ, BAGULEY BC, DENNY WA: Dimeric analogues of non-cationic tricyclic carboxamides are a new class of cytotoxic agents. Anticancer Drug Des. (1999) 14(3):281-289.
138. BRANA MF, RAMOS A: Naphthalimides as anti-cancer agents: synthesis and biological activity. Curr. Med. Chem. Anticancer Agents (2001) 1(3):237-255. Broad study of the cytotoxic activity of naphthalimides, leading to selection of elinafide.
139. BRANA M, WARING MJ, BAILLY C: Sequence-selective intercalation of antitumour bis-naphthalimides into DNA. Evidence for an approach via the major groove. Eur. J. Biochem. (1996) 240(1):195-208
140. GALLEGO J, REID BR: Solution structure and dynamics of a complex between DNA and the antitumor bisnaphthalimide LU-79553: intercalated ring flipping on the millisecond time scale. Biochemistry (1999) 38(46):15104-15115.
141. BOUSQUET PF, BRANA MF, CONLON D et al.: Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity. Cancer Res. (1995) 55(5):1176-1180.
142. VILLALONA-CALERO MA, EDER JP, TOPPMEYER DL et al.: Phase I and pharmacokinetic study of LU79553, a DNA intercalating bisnaphthalimide, in patients with solid malignancies. J. Clin. Oncol. (2001) 19(3):857-869.
143. AWADA A, THOEDTMANN R, PICCART M et al.: An EORTC-ECSG Phase I study of LU 79553 administered every 21 or 42 days in patients with solid tumors. Eur. J. Cancer (2003) 39(6):742-747. Full Phase I clinical trial report on elinafide.
144. MIMURA T, KATO N, SUGAYA T et al.: An efficient synthesis of a new class of DNA intercalating antitumor 7,10-dihydroxy-6H-pyrazolo[4,5,1-de]acridin-6-ones. Synthesis (1999) 6:947-952.
145. SAWYER M, RATAIN MJ, BERTUCCI DM, SCHILSKY RL, KUWABARA T, KINDLER HL: Pharmacokinetics and pharmacodynamics of KW 2170. Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 475).
146. SAIJO N, NAKAMURA T, MIZUKAMI T et al.: Effect of a novel pyrazoloacridone, KW-2170 on gene expression in various resistance cells determined by cDNA array. Proc. Am. Assoc. Cancer Res. (2000) 41 (Abstract 4587).
147. ASHIZAWA T, SHIMIZU M, GOMI K, OKABE M: Antitumor activity of KW-2170, a novel pyrazoloacridone derivative. Anticancer Drugs (1998) 9(3):263-271. Comparison of KW-2170 and doxorubicin in a wide range of human tumour xenografts.
148. KURAMITSU T, TAKAI K, OHASHI R, KUWABARA T: Determination of the anticancer drug KW-2170, a pyrazoloacridone derivative, and its metabolites in human and dog plasma by high-performance liquid chromatography using an electrochemical detector. J. Chromatog. B (2002) 768(2):231-237.
149. SAWYER MB, RATAIN MJ, BERTUCCI DM, KINDLER HL, SCHILSKY RL, KUWABARA T: Phase I studies of KW 2170 on two different schedules. Proc. Am. Soc. Clin. Oncol. (2001) 20 (Abstract 378).
150. SAEKI T, EGUCHI K, TAKASHIMA S et al.: Phase I study of KW-2170, a novel pyrazoloacridone compound against solid tumors. Proc. Am. Soc. Clin. Oncol. (2001) 20 (Abstract 2104).
151. VERSCHRAEGEN CF: KW-2170 (Kyowa Hakko Kogyo). IDrugs (2002) 5(10):1000-1003.
152. YOSHIDA M, KOBUNAI T, AOYAGI K et al.: Specific distribution of TOP-53 to the lung and lung-localized tumor is determined by its interaction with
153. BYL J, CLINE SD, UTSUGI T, KOBANAI T, YAMADA Y, OSHEROFF N: DNA topoisomerase II as the target for the anticancer drug TOP-53: Mechanistic basis for the drug action. Biochemistry (2001) 40(3):712-718. Comparison of topo II-mediated DNA cleavage by TOP-53 and etoposide.
154. UTSUGI T, SHIBATA J, SUGIMOTO Y: Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. Cancer Res. (1996) 56(12):2809-2814.
155. KOBUNAI T, SAITO H, YOSHIDA M, TOKO T, TAKEDA S, UNEMI N: In vitro and in vivo antitumor activity against lung cancer of TOP-53, a novel podophyllotoxin derivative. Proc. Am. Assoc. Cancer Res. (1994) 35:362 (Abstract 2154).
156. NAGAYAMA S, TSUDA M, KITAMURA R et al.: Tissue distribution of new anticancer drug TOP-53 in nude rats bearing human lung cancer. Proc. Am. Assoc. Cancer Res. (1997) 38:218 (Abstract 1466).
157. OHASHI Y, ISHIZUKA N, SUZUKI T, YAMAGUCHI T, MINAMI H, SASAKI Y: A hybrid design of pharmacokinetically guided dose escalation (PGDE) and continual reassessment method (CRM) in a Phase I trial of TOP-53. A new integrated approach using Bayesian concepts. Proc. Am. Assoc. Cancer Res. (1999) 40:82 (Abstract 545).
158. MINAMI H, SASAKI Y, OHASHI Y et al.: Clinical pharmacokinetics and pharmacodynamics of TOP-53 in comparison with dogs and mice. Proc. Am. Assoc. Cancer Res. (1999) 40:92 (Abstract 607).
159. KANEKO T, WONG H, UTZIG J, SCHURING J, DOYLE TW: Water soluble derivatives of rebeccamycin. J. Antibiot. (1990) 43(1):125-127.
160. LONG BH, ROSE WC, VYAS DM et al.: Discovery of antitumor indolocarbazoles: rebeccamycin, NSC 655649, and fluoroindolocarbazoles. Curr. Med. Chem. Anticancer Agents (2002) 2(2):255-266. Review of work leading to the selection on XL-119.
161. WEITMAN S, MOORE R, BARRERA H, CHEUNG NK, IZBICKA E, VON HOFF DD: In vitro antitumor activity of rebeccamycin analog (NSC 655649) against pediatric solid tumors. J. Pediatr. Hematol. Oncol. (1998) 20(2):136-139.
162. TOLCHER AW, ECKHARDT SG, KUHN J et al.: Phase I and pharmacokinetic study of NSC 655649, a rebeccamycin analog with topoisomerase inhibitory properties. J. Clin. Oncol. (2001) 19(11):2937-2947. Full report of Phase I clinical trial of XL-119.
163. DOWLATI A, HOPPEL CL, INGALLS ST et al.: Phase I clinical and pharmacokinetic study of rebeccamycin analog NSC 655649 given daily for five consecutive days. J. Clin. Oncol. (2001) 19(8):2309-2318.
164. AFSHI D, REMICK S, SUSA M et al.: A Phase I clinical and pharmacokinetic study of rebeccamycin analog (NSC-655649) given daily for five consecutive days. Proc. Am. Soc. Clin. Oncol. (1999) 18 (Abstract 694).
165. LANGEVIN A, WEITMAN S, JUHN S, BERNSTEIN M: A trial of rebeccamycin analog NSC-655649 in children with solid tumors: a Pediatric Oncology Group Phase I cooperative agreement study. Proc. Am. Soc. Clin. Oncol. (1999) 18 (Abstract 764).
166. HAMMOND LA, KUHN J, OCHOA L et al.: Phase I and pharmacokinetic (PK) trial of sequences of the rebeccamycin analog, NSC-655649, and cisplatin (CDDP). Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 380).
167. DOWLATI A, POSEY J, RAMANATHAN RK et al.: Multicenter Phase II and pharmacokinetic study of rebeccamycin analogue (RA) in advanced biliary cancers. Proc. Am. Soc. Clin. Oncol. (2003) 22:267 (Abstract 1070).
168. IBRAHIM D, HUSSAIN M, LORUSSO P, FLAHERTY L: Rebeccamycin analog (BMY-27557-14) in renal cell cancer (RCC): preliminary results of a Phase II trial. Proc. Am. Soc. Clin. Oncol. (2001) 20 (Abstract 2373).
169. CORTAS T, NESS A, CHAPMAN R et al.: Randomized Phase II trial of 2 different administration schedules of rebeccamycin analogue (RA) as 2nd line therapy in patients (pts) with advanced non-small cell lung cancer (NSCLC). Proc. Am. Soc. Clin. Oncol. (2003) 22:668 (Abstract 2686).
170. KON K, SUGI H, YAMADA N, TASHIRO T, TSURUO T: A novel antitumor agent IST-622; a chartreusin derivative. J. Cancer Res. Clin. Oncol. (1990) 116 (Suppl. Part 1).
171. KON K, AOYAMA Y, YAMAMOTO M et al.: Mechanism of action of IST-622 a novel antitumor antibiotic chartreusin analogue. Proc. Am. Assoc. Cancer Res. (1992) 33:514 (Abstract 3073).
172. TASHIRO T, KON K, YAMAMOTO M, YAMADA N, TSURUO T, TSUKAGOSHI S: Antitumor effects of IST-622, a novel synthetic derivative of chartreusin, against murine and human tumor lines following oral administration. Cancer Chemother. Pharmacol. (1994) 34(4):287-292.
173. ASAI G, YAMAMOTO N, TOI M et al.: Pharmacokinetic and pharmacodynamic study of IST-622, a novel synthetic derivative of chartreusin, by oral administration in a Phase II study of patients with breast cancer. Cancer Chemother. Pharmacol. (2002) 49(6):468-472. Full report of Phase II clinical trial of IST-622.
174. FORTUNE JM, VELEA L, GRAVES DE, UTSUGI T, YAMADA Y, OSHEROFF N: DNA topoisomerases as targets for the anticancer drug TAS-103: DNA interactions and topoisomerase catalytic inhibition. Biochemistry (1999) 38(47):15580-15586.
175. UTSUGI T, AOYAGI K, ASAO T et al.: Antitumor activity of a novel quinoline derivative, TAS-103, with inhibitory effects on topoisomerases I and II. Jap. J. Cancer Res. (1997) 88(10):992-1002.
176. BYL JAW, FORTUNE JM, BURDEN DA et al.: DNA topoisomerases as targets for the anticancer drug TAS-103: primary cellular target and DNA cleavage enhancement. Biochemistry (1999) 38(47):15573-15579. Detailed biochemical study showing that TAS-103 is a pure topo IIα inhibitor, not a dual topo I/II inhibitor as proposed earlier.
177. MINDERMAN H, WRZOSEK C, CAO S et al.: Mechanism of action of the dual topoisomerase-I and -II inhibitor TAS-103 and activity against (multi)drug resistant cells. Cancer Chemother. Pharmacol. (2000) 45(1):78-84.
178. OHYAMA T, LI Y, UTSUGI T et al.: A dual topoisomerase inhibitor, TAS-103, induces apoptosis in human cancer cells. Jpn. J. Cancer Res. (1999) 90(6):691-698.
179. AOYAGI Y, KOBUNAI T, UTSUGI T, WIERZBA K, YAMADA Y: Establishment and characterization of 6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one dihydrochloride (TAS-103)-resistant cell lines. Jpn. J. Cancer Res. (2000) 91(5):543-550.
180. KAWAGUCHI Y, YAMADA Y, TAJIMA K et al.: Optimal dosing method of TAS-103, a novel quinolone derivative inhibiting DNA topoisomerases. Proc. Am. Assoc. Cancer Res. (2001) 42 (Abstract 556).
181. AZUMA R, SAEKI M, YAMAMOTO Y, HAGIWARA Y, GROWCHOW LB, DONEHOWER RC: Metabolism and urinary excretion of a new quinoline anticancer drug, TAS-103, in humans. Xenobiotica (2002) 32(1):63-72.
182. DONEHOWER R, ELZA-BROWN K, O'REILLY S, ISRAEL B, GROCHOW L: A Phase I dose escalation, safety, tolerability and pharmacokinetic study of TAS-103 in patients with refractory solid tumors. Proc. Am. Soc. Clin. Oncol. (1998) 34 (Abstract 806).
183. EWESUEDO RB, IYER L, DAS S et al.: Phase I clinical and pharmacogenetic study of weekly TAS-103 in patients with advanced cancer. J. Clin. Oncol. (2001) 19(7):2084-2090. Full report of Phase I clinical trial showing QTc prolongation by TAS-103.
184. BURRIS HA, JONES SF, HAINSWORTH JD et al.: A Phase I study to determine the safety and pharmacokinetics of BMS-247615 administered once every week in patients with refractory solid tumors. Proc. Am. Soc. Clin. Oncol. (2000) 19 (Abstract 742).
185. HECK MMS, HITTELMAN WN, EARNSHAW WC: Differential expression of DNA topoisomerases I and II during the eukaryotic cell cycle. Proc. Natl. Acad. Sci. USA (1988) 85(4):1086-1090.
186. WHITACRE CM, ZBOROWSKA E, GORDON NH, MACKAY W, BERGER NA: Topotecan increases topoisomerase IIα levels and sensitivity to treatment with etoposide in schedule-dependent process. Cancer Res. (1997) 57(8):1425-1428.
187. HUCHET M, DEMARQUAY D, COULOMB H et al.: The dual topoisomerase inhibitor, BN 80927, is highly potent against cell proliferation and tumor growth. Ann. NY Acad. Sci. (2000) 922:303-305.
188. LAVERGNE O, HARNETT J, ROLLAND A et al.: BN 80927: a novel homocamptothecin with inhibitory activities on both topoisomerase I and topoisomerase II. Bioorg. Med. Chem. Lett. (1999) 9(17):2599-2602. Details of the topo inhibition and cell line cytotoxicity of BN-80927.
189. KASPRZYK PG, LAUER J, CARLSON M et al.: In vivo antitumor activity of a dual topoisomerase I/II inhibitor BN80927 against human tumor xenografts. Proc. Am. Assoc. Cancer Res. (2000) 41 (Abstract 5201).
190. LANSIAUX A, BAL C, WATTEZ N et al.: DNA macroarrays to identify genes responsive to apoptosis induced by the homocamptothecins BN80915 and BN80927. Proc. Am. Assoc. Cancer Res. (2002) 43:1086 (Abstract 5380).
191. UESUGI M, SEKIDA T, MATSUKI S, SUGIURA Y: Selective DNA cleavage by elsamicin A and switch function of its amino sugar group. Biochemistry (1991) 30(27):6711-6715.
192. LORICO A, LONG BH: Biochemical characterisation of elsamicin and other coumarin-related antitumour agents as potent inhibitors of human topoisomerase II. Eur. J. Cancer (1993) 29A(14):1985-1991.
193. RODRIGUEZ C, AZORIN F, PORTUGAL J: Influence of elsamicin A on the activity of mammalian topoisomerase I. Biochemistry (1996) 35(34):11177-11182.
194. GAVER RC, DEEB G, GEORGE AM: Validated HPLC procedures for the analysis of BMY-28090 in human plasma and urine. Cancer Chemother. Pharmacol. (1989) 25(3):195-201.
195. SCHURIG JE, BRADNER WT, BASLER GA, ROSE WC: Experimental antitumor activity of BMY-28090, a new antitumor antibiotic. Invest. New Drugs (1989) 7(203):173-178.
196. VERWEIJ J, WANDERS J, NIELSEN AL et al.: Phase II studies of Elsamitrucin in breast cancer, colorectal cancer, non-small cell lung cancer and ovarian cancer. Ann. Oncol. (1994) 5(4):375-376.
197. GOSS G, LETENDRE F, STEWART D et al.: Phase II study of eisamitrucin in non-small cell lung cancer. Invest. New Drugs (1994) 12(4):315-317.
198. ALLEN SL, SCHACTER LP, LICHTMAN SM et al.: Phase II study of elsamitrucin (BMY-28090) for the treatment of patients with refractory/relapsed non-Hodgkin's lymphoma. Invest. New Drugs (1996) 14(2):213-217. Full report of Phase II clinical trial of BN-80927.
199. SEBOLT JS, SCAVONE SV, PINTER CD et al.: Pyrazoloacridines, a new class of anticancer agents with selectivity against solid tumors in vitro. Cancer Res. (1987) 47(16):4299-4304.
200. ADJEI AA, CHARRON M, ROWINSKY EK et al.: Effect of pyrazoloacridine (NSC 366140) on DNA topoisomerases I and II. Clin. Cancer Res. (1998) 4(3):683-691.
201. GREM JL, POLITI PM, BALIS FM, SINHA BK, DAHUT W, ALLEGRA CJ: Cytotoxicity and DNA damage associated with pyrazoloacridine in MCF-7 breast cancer cells. Biochem. Pharmacol. (1996) 51(12):1649-1659.
202. CAPPS DB, DUNBAR J, KESTEN SR et al.: 2-(Aminoalkyl)-5-nitropyrazolo[3,4,5-kl]acridines, a new class of anticancer agents. J. Med. Chem. (1992) 35(26):4770-4778.
203. PALOMINO E, FOSTER B, KEMPFF M et al.: Identification and antitumor activity of a reduction product in the murine metabolism of pyrazoloacridine (NSC-366140). Cancer Chemother. Pharmacol. (1996) 38(5):453-458.
204. FOSTER BJ, WIEGAND RA, LORUSSO PM, BAKER LH: Pharmacokinetics of 9-methoxy-N,N-dimethyl-5-nitropyrazolo [3,4,5-kl]acridine-2(6H)-propanamine (PZA, PD 115934, NSC 366140) in mice: guidelines for early clinical trials. Clin. Cancer Res. (1995) 1(8):831-837.
205. BERG SL, BLANEY SM, ADAMSON PC et al.: Phase I trial and pharmacokinetic study of pyrazoloacridine in children and young adults with refractory cancers. J. Clin. Oncol. (1998) 16(1):181-186.
206. KUEBLER J, KING GW, TRIOZZI P, MOORE T, KRAUT EH: Phase II study of pyrazoloacridine in metastatic renal cell carcinoma. Invest. New Drugs (2001) 19:327-328.
207. PLAXE SC, BLESSING JA, MORGAN MA, CARLSON J: Phase II trial of pyrazoloacridine in recurrent platinum-resistant ovarian cancer: a Gynecologic Oncology Group study. Am. J. Clin. Oncol. (2002) 25:45-47.
208. PELLEY R, GANAPATHI R, WOOD L et al.: A Phase II pharmacodynamic study of pyrazoloacridine in patients with metastatic colorectal cancer. Cancer Chemother. Pharmacol. (2000) 46(3):251-254.
209. ZALUPSKI MM, SHIELDS AF, PHILIP PA et al.: Evaluation of pyrazoloacridine in patients with advanced pancreatic carcinoma. Invest. New Drugs. (1998) 16(1):93-96.
210. PLAXE SC, BLESSING JA, LUCCI JA, HURTEAU JA: A Phase II trial of pyrazoloacridine (PZA) in squamous carcinoma of the cervix. Invest. New Drugs (2001) 19(1):77-80.
211. PLAXE SC, BLESSING JA, HUSSEINZADEH N, WEBSTER KD, RADER JS, DUNTON CJ: Phase II trial of pyrazoloacridine in patients with persistent or recurrent endometrial carcinoma: a Gynecologic Oncology Group Study. Gym. Oncol. (2002) 84(2):241-244.
212. SMALL EJ, FIPPIN LJ, WHISENANT SP: Pyrazoloacridine for the treatment of hormone-refractory prostate cancer. Cancer Inv. (1998) 16(7):456-461.
213. BASTASCH M, PANELLA TJ, KRETZSCHMER S, GRAHAM D, MAYO M, WILLIAMSON S: Phase II trial of pyrazoloacridine in advanced non-small cell carcinoma of the lung. Invest. New Drugs (2002) 20(3):339-342.
214. BERG SL, BLANEY SM, SULLIVAN J, BERNSTEIN M, DUBOWY R, HARRIS M: Phase II trial of pyrazoloacridine in children with solid tumors: a Pediatric Oncology Group Phase II study. J. Pediatr. Haematol. Oncol. (2000) 22(6):506-509.
215. KESHELAVA N, TSAO-WEI D, REYNOLDS CP: Pyrazoloacridine is active in multidrug-resistant neuroblastoma cell lines with nonfunctional p53. Clin. Cancer Res. (2003) 9(9):3492-3502. Cell line study suggesting a new role for pyrazoloacridine in brain tumours.
216. LESSER GJ, CARSON K, PRIET R, NABORS LB, DOYLE T, GROSSMAN SA: A Phase I/II trial of pyrazoloacridine (PZA) in adults with newly diagnosed glioblastoma multiforme (GBM). Proc. Am. Soc. Clin. Oncol. (2002) 21 (Abstract 2097).
217. ADJEI A, REID J, ERLICHMAN C et al.: A Phase I and pharmacologic study of pyrazoloacridine (NSC 366140) and carboplatin in patients with advanced cancer. Invest. New Drugs (2002) 0(3):297-304.
218. CLAIRE DE, ROWINSKY EK, NOE DA et al.: A Phase I and pharmacologic study of pyrazoloacridine and cisplatin in patients with advanced cancer. Invest. New Drugs (2003) 21(1):75-84.
219. BARRET JM, MONTAUDON D, ETIEVANT C et al.: Detection of DNA-strand breaks in cells treated with F 11782, a catalytic inhibitor of topoisomerases I and II. Anticancer Res. (2000) 20(6B):4557-4562.
220. PERRIN D, VAN HILLE B, BARRET JM et al.: F 11782, a novel epipodophylloid non-intercalating dual catalytic inhibitor of topoisomerases I and II with an original mechanism of action. Biochem. Pharmacol. (2000) 59(7):807-819.
221. BARRET JM, LIMOUZY A, LACASTAIGNERATTE L, HILL BT: Characterization using the TARDIS assay of the effects of F 11782 on cleavable complex formation in V79 cultured cells. Proc. Am. Assoc. Cancer Res. (2002) 43:249 (Abstract 1237).
222. WALKER JV, NITISS KC, BARRET JM, HILL BT, NITISS JL: The epipodophyllotoxin derivative F 11782 causes an novel mode of inhibition of topoisomerase II. Proc. Am. Assoc. Cancer Res. (2002) 43:250 (Abstract 1249).
223. BARRETT JM, MENON Y, CREANCIER L, LACASTAIGNERATTE L, HILL BT: Identification of homology with topoisomerases and XPG which might explain the interactions of F 11782 on these proteins. Proc. Am. Assoc. Cancer Res. (2003) 44:406 (Abstract 1788).
224. BARRET JM, ETIEVANT C, BAUDOUIN C, SKOV K, CHARVERON M, HILL BF: F 11782, a novel catalytic inhibitor of topoisomerases I and II, induces atypical, yet cytotoxic DNA double-strand breaks in CHO-K1 cells. Anticancer Res. (2002) 22(1A):187-192. Report of atypical DNA breakage activity of tafluposide.
225. BARRET JM, HILL BT, OLIVE PL: Characterization of DNA-strand breakage induced in V79 cells by F 11782, a catalytic inhibitor of topoisomerases. Br. J. Cancer (2000) 83(12):1740-1746.
226. KRUCZYNSKI A, ETIEVANT C, PERRIN D, IMBERT T, COLPAERT F, HILL BT: Preclinical antitumour activity of F 11782, a novel dual catalytic inhibitor of topoisomerases. Br. J. Cancer (2000) 83(11):1516-1524.
227. BARRET JM, KRUCZYNSKI A, ETIEVANT C, HILL BT: Synergistic effects of F 11782, a novel dual inhibitor of topoisomerases I and II, in combination with other anticancer agents. Cancer Chemother. Pharmacol. (2002) 49(6):479-486. Extensive cell culture studies showing synergy of talfluposide with other cytotoxics.
228. SARGENT JM, ELGIE AW, WILLIAMSON CJ, HILL BT: Ex vivo effects of the dual topoisomerase inhibitor tafluposide (F 11782) on cells isolated from fresh tumor samples taken from patients with cancer. Anticancer Drugs (2003) 16(6):467-473.
229. VICKER N, BURGESS L, CHUCKOWREE IS et al.: Novel angular benzophenazines: dual topoisomerase I and topoisomerase II inhibitors as potential anticancer agents. J. Med. Chem. (2002) 45(3):721-739.
230. GAMAGE SA, SPICER JA, MILTON J et al.: Structure-activity relationships for pyrido-, imidazo-, pyrazolo-, pyrazino- and pyrrolophenazinecarboxamides as topoisomerase-targeted anticancer agents. J. Med. Chem. (2002) 45(3):740-743.
231. WANG S, MILLER W, MILTON J, VICKER N et al.: Structure-activity relationships for analogues of the phenazine-based dual topoisomerase I/II inhibitor XR11576. Bioorg. Med. Chem. Lett. (2002) 12:415-418.
232. MISTRY P, STEWART AJ, DANGERFIELD W et al.: In vitro and in vivo characterisation of XR11576, a novel, orally active, dual inhibitor of topoisomerase I and II. Anticancer Drugs, (2002) 13(1):15-28. Detailed mechanism of action studies on XR-11576.
233. JOBSON A, WILLMORE E, TILBY M, MISTRY P, CHARLTON P, AUSTIN C: Characterisation of the roles of Topoisomerase I and II in the mechanism of action of the novel anti-tumour agent XR11576 (MLN576). Proc. Am. Assoc. Cancer Res. (2003) 44:363 (Abstract 1601).
234. MCRIPLEY RJ, BURNS-HORWITZ PE, CZERNIAK PM et al.: Efficacy of DMP 840: a novel bis-naphthalimide cytotoxic agent with human solid tumor xenograft selectivity. Cancer Res. (1994) 54(1):159-164.
235. THOMPSON J, PRATT CB, STEWART CF et al.: A Phase I study of DMP 840 in pediatric patients with refractory solid tumors. Invest. New Drugs (1998) 16(1):45-49.
236. GAMAGE SA, SPICER JA, FINLAY GJ et al.: Dicationic bis(9-methylphenazine-1-carboxamides): relationships between biological activity and linker chain structure for a series of potent topoisomerase-targeted anticancer drugs. J. Med. Chem. (2001) 44(9):1407-1415. SAR studies leading to the selection of MLN-944.
237. SPICER JA, GAMAGE SA, REWCASTLE GW et al.: bis(phenazine-1-carboxamides): structure-activity relationships for a new class of dual topoisomerase I/II-directed anticancer drugs. J. Med. Chem. (2000) 43(7):1350-1358.
238. STEWART AJ, MISTRY P, DANGERFIELD W et al.: Antitumor activity of XR5944, a novel and potent topoisomerase poison. Anticancer Drugs (2001) 12:359-367. Demonstration of topo I- and II-induced DNA breakage by MLN-944.
239. LEWIS LJ, CHARLTON PA, MISTRY P, THOMAS H, COLEY HM: Cellular characterisation and differentiation of XR5944 (MLN944) from XR11576 (MLN576), two novel DNA targeting agents. Proc. Am. Assoc. Cancer Res. (2003) 44:406 (Abstract 1787).
240. SAPPAL DS, MISTRY P, RUDOLPH OWEN LA: MLN944 (XR5944) regulates cell cycle progression by a novel mechanism compared to known topoisomerase inhibitors. Proc. Am. Assoc. Cancer Res. (2003) 44:634 (Abstract 2780).
241. FLEMMING JA, BLACKMAN RK, THORODDSEN V, RUDOLPH-OWEN R, CHARLTON P, BULAWA C: Using yeast to probe the mechanism of action of MLN944 (XR5944), a novel bis-phenazine with potent anti-tumor activity. Proc. Am. Assoc. Cancer Res. (2003) 44:1506 (Abstract 6574).
242. FREATHY C, DANGERFIELD W, SAPPAL DS et al.: Comparison of the cellular exposure time of XR5944 (MLN944) and known topoisomerase inhibitors required to induce cell cycle arrest, apoptosis and ultimate cell death. Proc. Am. Assoc. Cancer Res. (2003) 44:835 (Abstract 3652).