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Chemical Compound Review

Amsidine     N-[4-(acridin-9-ylamino)-3- methoxy...

Synonyms: Amsidyl, amsacrine, m-AMSA, AMSA P-D, NSC-141549, ...
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Disease relevance of Amsidyl

  • Treatment of SV40 virus infected monkey cells with m-AMSA resulted in both single- and double-stranded breaks on SV40 viral chromatin [1].
  • Sensitivities to m-AMSA did not differ significantly between normal marrow and blood CFC, between normal and CML CFC, or between CML CFC obtained from patients with leukemias in chronic phase and blast transformation [2].
  • Derivatives of amsacrine: determinants required for high activity against Lewis lung carcinoma [3].
  • Because the development of resistance to cancer chemotherapeutic agents represents a major limitation of cancer chemotherapy, we investigated the mechanism of resistance by murine P388 leukemia to camptothecin (topoisomerase I inhibitor) or amsacrine (topoisomerase II inhibitor) [4].
  • Because the bacteriophage T4-encoded topoisomerase resembles the mammalian enzyme, we are using T4 as a simple model system to investigate the mechanism of action of m-AMSA [5].

High impact information on Amsidyl

  • These cells were also markedly sensitive to mitoxantrone, amsacrine, and etoposide (drugs that induce double-strand breaks) (two-sided P = .002) and to ionizing radiation (two-sided P = .001) [6].
  • Resistant cell lines were derived by exposure to either amsacrine or doxorubicin [7].
  • However, when the substituents on the anilino side chain of amsacrine were changed, the in vitro cross-resistance of the P/AMSA line could be substantially reduced and even overcome [8].
  • Four main patterns were evident: a transport-related multidrug-resistance pattern (three sublines), a pattern similar to that for a murine P388 leukemia subline resistant to amsacrine, and two patterns not observed previously [7].
  • The difference between the HT1080 and DR4 lines in AMSA- and 5-iminodaunorubicin-induced cleavage was similar in cells and nuclei and could be due to the lower amount of DR4 topoisomerase II [9].

Chemical compound and disease context of Amsidyl


Biological context of Amsidyl

  • A survey of 115 analogues of amsacrine indicates that a low ratio of IC50 values (HCT-8/L1210) is necessary but not sufficient for good antitumor activity against the solid tumor [3].
  • Considerable variations in resistance factors were noted for each cell subline as the amsacrine substituents were altered [7].
  • In addition, the gene 39 subunit from the m-AMSA-resistant mutant phage has an altered net charge, strongly indicating that the drug-resistance mutation is within gene 39 [5].
  • The agreement between in vitro and in vivo studies suggests that mammalian DNA topoisomerase II may be the primary target of m-AMSA and that the drug-induced complex formation between topoisomerase II and DNA may be the cause of cytotoxicity and other effects such as DNA sequence rearrangements and sister-chromatid exchange [14].
  • It was demonstrated that transient exposure to low concentrations of amsacrine inhibited replicon initiation but did not substantially affect DNA chainelongation within operating replicons [15].

Anatomical context of Amsidyl

  • Exposure to amsacrine or etoposide caused at least 50-fold less DNA cleavage in CLL and normal lymphocytes as compared to L1210 cells [16].
  • The fact that these breaks reverse rapidly in cells programmed to die, led us to investigate further the cytotoxic mechanisms of topoisomerase I (camptothecin) and topoisomerase II inhibitors (VP-16 and amsacrine) in Chinese Hamster lung fibroblasts (DC3F) [17].
  • To determine whether topoisomerase II poisons that produce double-strand breaks by trapping of cleavable complexes would, likewise, induce mutations specific to plateau-phase cells, aprt mutations induced by amsacrine in both log-phase and plateau-phase CHO cells were analyzed [18].
  • The results of fractionation of nuclear DNA show that m-AMSA induces 20- to 45-fold more DPC in nuclear matrix-associated DNA than in the majority distal loop DNA, supporting the notion that topoisomerase II is located at the nuclear matrix [19].
  • The frequency of DNA strand breaks induced by amsacrine was higher (1.5- to 13-fold) in the testis cells than in the bladder cells [20].

Associations of Amsidyl with other chemical compounds


Gene context of Amsidyl


Analytical, diagnostic and therapeutic context of Amsidyl


  1. In vivo mapping of DNA topoisomerase II-specific cleavage sites on SV40 chromatin. Yang, L., Rowe, T.C., Nelson, E.M., Liu, L.F. Cell (1985) [Pubmed]
  2. Chemotherapeutic sensitivity of normal and leukemic hematopoietic progenitor cells to N-[4-(9-acridinylamino)-3-methoxyphenyl]-methanesulfonamide, a new anticancer agent. Spiro, T.E., Socquet, M., Delforge, A., Stryckmans, P. J. Natl. Cancer Inst. (1981) [Pubmed]
  3. Derivatives of amsacrine: determinants required for high activity against Lewis lung carcinoma. Baguley, B.C., Finlay, G.J. J. Natl. Cancer Inst. (1988) [Pubmed]
  4. Nonproductive rearrangement of DNA topoisomerase I and II genes: correlation with resistance to topoisomerase inhibitors. Tan, K.B., Mattern, M.R., Eng, W.K., McCabe, F.L., Johnson, R.K. J. Natl. Cancer Inst. (1989) [Pubmed]
  5. Bacteriophage T4 DNA topoisomerase is the target of antitumor agent 4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA) in T4-infected Escherichia coli. Huff, A.C., Leatherwood, J.K., Kreuzer, K.N. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  6. Double-strand break repair deficiency and radiation sensitivity in BRCA2 mutant cancer cells. Abbott, D.W., Freeman, M.L., Holt, J.T. J. Natl. Cancer Inst. (1998) [Pubmed]
  7. Multiple patterns of resistance of human leukemia cell sublines to amsacrine analogues. Finlay, G.J., Baguley, B.C., Snow, K., Judd, W. J. Natl. Cancer Inst. (1990) [Pubmed]
  8. Design of DNA intercalators to overcome topoisomerase II-mediated multidrug resistance. Baguley, B.C., Holdaway, K.M., Fray, L.M. J. Natl. Cancer Inst. (1990) [Pubmed]
  9. HT1080/DR4: a P-glycoprotein-negative human fibrosarcoma cell line exhibiting resistance to topoisomerase II-reactive drugs despite the presence of a drug-sensitive topoisomerase II. Zwelling, L.A., Slovak, M.L., Doroshow, J.H., Hinds, M., Chan, D., Parker, E., Mayes, J., Sie, K.L., Meltzer, P.S., Trent, J.M. J. Natl. Cancer Inst. (1990) [Pubmed]
  10. Localization of an aminoacridine antitumor agent in a type II topoisomerase-DNA complex. Freudenreich, C.H., Kreuzer, K.N. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  11. Amsacrine with high-dose cytarabine is highly effective therapy for refractory and relapsed acute lymphoblastic leukemia in adults. Arlin, Z.A., Feldman, E., Kempin, S., Ahmed, T., Mittelman, A., Savona, S., Ascensao, J., Baskind, P., Sullivan, P., Fuhr, H.G. Blood (1988) [Pubmed]
  12. Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia. Kaufmann, S.H., Karp, J.E., Jones, R.J., Miller, C.B., Schneider, E., Zwelling, L.A., Cowan, K., Wendel, K., Burke, P.J. Blood (1994) [Pubmed]
  13. Pharmacokinetic and toxicity scaling of the antitumor agents amsacrine and CI-921, a new analogue, in mice, rats, rabbits, dogs, and humans. Paxton, J.W., Kim, S.N., Whitfield, L.R. Cancer Res. (1990) [Pubmed]
  14. Mechanism of antitumor drug action: poisoning of mammalian DNA topoisomerase II on DNA by 4'-(9-acridinylamino)-methanesulfon-m-anisidide. Nelson, E.M., Tewey, K.M., Liu, L.F. Proc. Natl. Acad. Sci. U.S.A. (1984) [Pubmed]
  15. Inhibition of replicon initiation in human cells following stabilization of topoisomerase-DNA cleavable complexes. Kaufmann, W.K., Boyer, J.C., Estabrooks, L.L., Wilson, S.J. Mol. Cell. Biol. (1991) [Pubmed]
  16. Resistance of human leukemic and normal lymphocytes to drug-induced DNA cleavage and low levels of DNA topoisomerase II. Potmesil, M., Hsiang, Y.H., Liu, L.F., Bank, B., Grossberg, H., Kirschenbaum, S., Forlenza, T.J., Penziner, A., Kanganis, D., Forlenzar, T.J. Cancer Res. (1988) [Pubmed]
  17. Differential requirement of DNA replication for the cytotoxicity of DNA topoisomerase I and II inhibitors in Chinese hamster DC3F cells. Holm, C., Covey, J.M., Kerrigan, D., Pommier, Y. Cancer Res. (1989) [Pubmed]
  18. Enhanced amsacrine-induced mutagenesis in plateau-phase Chinese hamster ovary cells, with targeting of +1 frameshifts to free 3' ends of topoisomerase II cleavable complexes. Patteson, K., Wang, P., Povirk, L.F. Cancer Res. (1999) [Pubmed]
  19. Comparison of DNA-protein cross-links induced by 4'-(9-acridinylamino)-methanesulfon-m-anisidide and by gamma-radiation. Chiu, S.M., Xue, L.Y., Friedman, L.R., Oleinick, N.L. Cancer Res. (1989) [Pubmed]
  20. Relationship between topoisomerase II level and chemosensitivity in human tumor cell lines. Fry, A.M., Chresta, C.M., Davies, S.M., Walker, M.C., Harris, A.L., Hartley, J.A., Masters, J.R., Hickson, I.D. Cancer Res. (1991) [Pubmed]
  21. Experimental antitumor activity of the amsacrine analogue CI-921. Leopold, W.R., Corbett, T.H., Griswold, D.P., Plowman, J., Baguley, B.C. J. Natl. Cancer Inst. (1987) [Pubmed]
  22. Intercalators promote the binding of RecA protein to double-stranded DNA. Thresher, R.J., Griffith, J.D. Proc. Natl. Acad. Sci. U.S.A. (1990) [Pubmed]
  23. Genetic transfer of non-P-glycoprotein-mediated multidrug resistance (MDR) in somatic cell fusion: dissection of a compound MDR phenotype. Eijdems, E.W., Borst, P., Jongsma, A.P., de Jong, S., de Vries, E.G., van Groenigen, M., Versantvoort, C.H., Nieuwint, A.W., Baas, F. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  24. Suramin is an inhibitor of DNA topoisomerase II in vitro and in Chinese hamster fibrosarcoma cells. Bojanowski, K., Lelievre, S., Markovits, J., Couprie, J., Jacquemin-Sablon, A., Larsen, A.K. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  25. Amsacrine and etoposide hypersensitivity of yeast cells overexpressing DNA topoisomerase II. Nitiss, J.L., Liu, Y.X., Harbury, P., Jannatipour, M., Wasserman, R., Wang, J.C. Cancer Res. (1992) [Pubmed]
  26. A unique human ovarian carcinoma cell line expressing CD34 in association with selection for multidrug resistance. Minderman, H., Vanhoefer, U., Toth, K., Minderman, M.D., Rustum, Y.M. Cancer (1996) [Pubmed]
  27. Free radical scavengers can differentially modulate the genotoxicity of amsacrine in normal and cancer cells. Blasiak, J., Gloc, E., Drzewoski, J., Wozniak, K., Zadrozny, M., Skórski, T., Pertynski, T. Mutat. Res. (2003) [Pubmed]
  28. Progressive resistance to doxorubicin in mouse leukemia L1210 cells with multidrug resistance phenotype: reductions in drug-induced topoisomerase II-mediated DNA cleavage. Ganapathi, R., Grabowski, D., Ford, J., Heiss, C., Kerrigan, D., Pommier, Y. Cancer Commun. (1989) [Pubmed]
  29. The human multidrug resistance-associated protein MRP is a plasma membrane drug-efflux pump. Zaman, G.J., Flens, M.J., van Leusden, M.R., de Haas, M., Mülder, H.S., Lankelma, J., Pinedo, H.M., Scheper, R.J., Baas, F., Broxterman, H.J. Proc. Natl. Acad. Sci. U.S.A. (1994) [Pubmed]
  30. Long-term survival in refractory acute myeloid leukemia after sequential treatment with chemotherapy and reduced-intensity conditioning for allogeneic stem cell transplantation. Schmid, C., Schleuning, M., Schwerdtfeger, R., Hertenstein, B., Mischak-Weissinger, E., Bunjes, D., Harsdorf, S.V., Scheid, C., Holtick, U., Greinix, H., Keil, F., Schneider, B., Sandherr, M., Bug, G., Tischer, J., Ledderose, G., Hallek, M., Hiddemann, W., Kolb, H.J. Blood (2006) [Pubmed]
  31. Toxicity of 4'-(9-acridinylamino)methanesulfon-m-anisidide in exponential- and plateau-phase Chinese hamster cell cultures. Wilson, W.R., Giesbrecht, J.L., Hill, R.P., Whitmore, G.F. Cancer Res. (1981) [Pubmed]
  32. Amsacrine-associated cardiotoxicity: an analysis of 82 cases. Weiss, R.B., Grillo-López, A.J., Marsoni, S., Posada, J.G., Hess, F., Ross, B.J. J. Clin. Oncol. (1986) [Pubmed]
  33. Disposition of amsacrine and its analogue 9-([2-methoxy-4-[(methylsulfonyl)amino]phenyl]amino)-N,5-dimethyl-4- acridinecarboxamide (CI-921) in plasma, liver, and Lewis lung tumors in mice. Kestell, P., Paxton, J.W., Evans, P.C., Young, D., Jurlina, J.L., Robertson, I.G., Baguley, B.C. Cancer Res. (1990) [Pubmed]
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