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Japanese Journal of Cancer Research : Gann logoLink to Japanese Journal of Cancer Research : Gann
. 1990 Aug;81(8):842–849. doi: 10.1111/j.1349-7006.1990.tb02654.x

Menogaril, an Anthracycline Compound with a Novel Mechanism of Action: Cellular Pharmacology

Konstanty Wierzba 1, Yoshikazu Sugimoto 1, Ken‐ichi Matsuo 1, Toshiyuki Toko 1, Setsuo Takeda 1, Yuji Yamada 1, Shigeru Tsukagoshi 2
PMCID: PMC5918082  PMID: 2144516

Abstract

Menogaril, an anthracycline compound possessing a significant antitumor activity after both po and iv administration, has been introduced into clinical trials. However, its mechanism of action has not been clarified yet. This study revealed that its cytotoxicity correlated very well with the inhibition of macromolecular synthesis, indicating the involvement of interaction with DNA. The spectrophotometric study showed a weaker binding of this compound to calf thymus DNA when compared to that of doxorubicin (adriamycin). Despite the lower binding affinity of menogaril to DNA, pronounced DNA cleavage was observed in an intact cell system, indicating that the character of the interaction with DNA is different from intercalation. In contrast to doxorubicin, menogaril is extensively localized in the cytoplasm. The cytoplasmic localization prompted us to study its effect on cytoskeleton proteins. It was found that menogaril inhibited the initial polymerization rate of tubulin, indicating a possible contribution of this process to the overall cytotoxicity of menogaril.

Keywords: Menogaril, Interaction with DNA, Microtubular system, Anthracycline compound

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REFERENCES

  • 1. ) Wiley , P. P. , Elrod , D. W. , Houser , D. J. and Richard , F. A.Structure‐activity relationship of nogalamycin analogues . J. Med. Chem. , 25 , 560 – 567 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 2. ) Neil , G. L. , Keuntzel , S. L. and McGovren , J. P.Treatment of mouse tumors with 7‐con‐O‐methylnogarol and other analogs of anthracycline antibiotic nogalamycin . Cancer Treat. Rep. , 39 , 4816 – 4822 ( 1979. ). [PubMed] [Google Scholar]
  • 3. ) Kreuger , W. C. , Pschigoda , L. M. , Schpok , S. L. F. , Moscotitz , A. , McGovren , J. P. , Neta , P. , Merritt , M. V. and Li , L. H.The interaction of nogalamycin and analogs with DNA and other biopolymers . Chem.-Biol. Interact. , 36 , 1 – 18 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 4. ) Bhuyan , B. K. , McGovren , J. P. and Crampton , S. L.Intracellular uptake of 7‐con‐methylnogarol and adriamycin by cells in culture and its relationship to cell survival . Cancer Res. , 41 , 882 – 887 ( 1981. ). [PubMed] [Google Scholar]
  • 5. ) Egorin , M. J. , Clawson , R. E. , Cohen , J. L. , Ross , L. A. and Bachur , N. R.Cytofluorescence localization of anthracycline antibiotics . Cancer Res. , 40 , 4669 – 4676 ( 1980. ). [PubMed] [Google Scholar]
  • 6. ) DuVernay , V. H. , Pachter , J. A. and Crooke , S. T.DNA binding studies on several new anthracycline antitumor antibiotics II. The importance of the carbomethoxy‐group at position‐10 of the class II anthracycline molecule . Mol. Pharmacol. , 16 , 623 – 632 ( 1979. ). [PubMed] [Google Scholar]
  • 7. ) Vogel , D. G. , Margolis , R. L. and Mottet , N. K.The effects of methyl mercury binding to microtubules . Toxicol. Appl. Pharmacol , 80 , 473 – 486 ( 1985. ). [DOI] [PubMed] [Google Scholar]
  • 8. ) Wierzba , K. , Sugiyama , Y. , Okudaira , K. , Iga , T. and Hanano , M.Tubulin as a major determinant of tissue distribution of vincristine . J. Pharm. Sci. , 76 , 872 – 875 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 9. ) Wierzba , K. , Sugiyama , Y. , Iga , T. and Hanano , M.Kinetic study on the mechanism of tissue distribution of vinblastine . J. Pharmacobio-Dyn. , 11 , 651 – 661 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 10. ) Barcelo , F. , Martorell , J. , Gavilanes , F. and Gonzales‐Ros , J. M.Equilibrium binding of daunomycin and adriamycin to calf thymus DNA. Temperature and ionic strength dependence of thermodynamic parameters . Biochem. Pharmacol. , 37 , 2133 – 2138 ( 1988. ). [DOI] [PubMed] [Google Scholar]
  • 11. ) Byrn , S. R. and Dolch , G. D.Analysis of binding of daunorubicin and doxorubicin to DNA using computerized curve‐fitting procedure . J. Pharm. Sci. , 67 , 688 – 693 ( 1978. ). [DOI] [PubMed] [Google Scholar]
  • 12. ) Yamaoka , K. , Tanigawara , Y. , Nakagawa , T. and Uno , T.A pharmacokinetic analysis program (MULTI) for micro‐computer . J. Pharmacobio-Dyn , 4 , 879 – 885 ( 1981. ). [DOI] [PubMed] [Google Scholar]
  • 13. ) Yoshioka , A. , Tanaka , S. , Hiraoka , O. , Koyama , Y. , Hirota , Y. , Ayusawa , D. , Seno , T. , Garrett , C. and Wataya , Y.Deoxyribonucleoside triphosphate imbalance. 5‐Fluorodeoxyuridine‐induced DNA double strand breaks in FM3A cells and the mechanism of cell death . J. Biol. Chem. , 262 , 8235 – 8241 ( 1987. ). [PubMed] [Google Scholar]
  • 14. ) Yoshioka , A. , Tanaka , S. , Hiraoka , O. , Koyama , Y. , Hirota , Y. and Wataya , Y.Deoxyribonucleoside‐triphosphate imbalance death: deoxyadenosine‐induced dNTP imbalance and DNA double strand breaks in mouse FM3A cells and mechanism of cell death . Biochem. Biophys. Res. Commun. , 146 , 258 – 264 ( 1987. ). [DOI] [PubMed] [Google Scholar]
  • 15. ) Hirota , Y. , Yoshioka , A. , Tanaka , S. , Watanabe , K. , Otani , T. , Minowada , J. , Matsuda , A. , Ueda , T. and Wataya , Y.Imbalance of deoxyribonucleoside triphosphates, DNA double‐strand breaks and cell death caused by 2‐chlorodeoxyadenosine in mouse FM3A cells . Cancer Res. , 49 , 915 – 919 ( 1989. ). [PubMed] [Google Scholar]
  • 16. ) Egorin , M. J. , Clawson , R. E. , Cohen , J. L. , Ross , L. A. and Bachur , N. R.Cellular pharmacology of 7(R)‐O‐methylnogarol: a new anticancer agent . J. Pharmacol. Exp. Ther. , 210 , 229 – 236 ( 1979. ). [PubMed] [Google Scholar]
  • 17. ) Misumi , M. , Yamaki , H. , Akiyama , T. and Tanaka , N.Mechanism of action of aclacinomycin. II. The interaction with DNA and with tubulin . J. Antibiot. , 32 , 48 – 52 ( 1979. ). [DOI] [PubMed] [Google Scholar]
  • 18. ) Li , L. H. , Kuentzel , S. L. , Murch , L. L. , Pschigoda , L. M. and Krueger , W. C.Comparative biological and biochemical effects of nogalamycin and its analogs on L1210 leukemia . Cancer Res. , 39 , 4816 – 4822 ( 1979. ). [PubMed] [Google Scholar]
  • 19. ) Chaires , J. B. , Battagupta , N. and Crothers , D. M.Studies on interaction of anthracycline antibiotics and deoxy‐nucleic acid. Equilibrium binding studies on interaction of daunomycin with deoxyribonucleic acid . Biochemistry , 21 , 3933 – 3940 ( 1982. ). [DOI] [PubMed] [Google Scholar]
  • 20. ) Wozniak , A. J. and Ross , W. E.DNA damage as a basis for 4‐demethylepipodophyllotoxin‐9‐ (4,6‐O‐ethylidene‐b‐d‐glucopyranoside) (Etoposide) cytotoxicity . Cancer Res. , 43 , 120 – 124 ( 1983. ). [PubMed] [Google Scholar]
  • 21. ) Smith , P. J. and Makinson , T. A.Cellular consequences of overproduction of DNA topoisomerase II in an ataxia‐telagiectasia cell line . Cancer Res. , 49 , 1118 – 1124 ( 1989. ). [PubMed] [Google Scholar]
  • 22. ) Spiridonidis , C. A. , Chatterjee , S. , Petzold , S. J. and Berger , N. A.Topoisomerase II‐dependent and ‐independent mechanisms of etoposide resistance to Chinese hamster cell lines . Cancer Res. , 49 , 644 – 650 ( 1989. ). [PubMed] [Google Scholar]
  • 23. ) Markovits , J. , Pommier , Y. , Kerrigan , D. , Covey , J. M. , Tilchen , E. J. and Kohn , K. W.Topoisomerase II‐mediated DNA breaks and cytotoxicity in relation to cell proliferation, cell death and the cell cycle in NIH3T3 fibroblasts and L1210 leukemia cells . Cancer Res. , 47 , 2050 – 2055 ( 1987. ). [PubMed] [Google Scholar]
  • 24. ) Lawrence , T. S.Reduction of doxorubicin cytotoxicity by ouabain: correlation with topoisomerase‐induced DNA strand breakage in human and hamster cells . Cancer Res. , 48 , 725 – 730 ( 1988. ). [PubMed] [Google Scholar]

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