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. 1994 Feb;69(2):315–319. doi: 10.1038/bjc.1994.57

L1210 cells selected for resistance to methoxymorpholinyl doxorubicin appear specifically resistant to this class of morpholinyl derivatives.

C Geroni 1, E Pesenti 1, M Broggini 1, G Belvedere 1, G Tagliabue 1, M D'Incalci 1, G Pennella 1, M Grandi 1
PMCID: PMC1968686  PMID: 8297727

Abstract

We investigated the mechanism of resistance in murine L1210 leukaemia cells selected after treatment with FCE 23762 methoxymorpholinyl doxorubicin: (MMRDX), a methoxymorpholinyl derivative of doxorubicin active in vitro and in vivo on multidrug-resistant (mdr) cells, currently undergoing phase I clinical trials. The resistant subline obtained after repeated in vitro treatments, L1210/MMRDX, is resistant in vitro and in vivo to all tested methoxymorpholinyl derivatives and to cyanomorpholinyl doxorubicin, but shows resistance to morpholinyl derivatives only in vivo or following their activation with rat S9-liver fractions in vitro. L1210/MMRDX cells are sensitive to classic mdr- and altered topoisomerase (AT)-mdr-associated drugs. These cells do not appear to overexpress the mdr1 gene, nor do they exhibit impaired intracellular drug accumulation and efflux or altered levels of glutathione and glutathione S-transferase. The extent of DNA single-strand break formation and, after microsomal activation, of DNA interstrand cross-links after treatment with MMRDX was similar in the parent and the resistant subline. The mechanism of resistance in L1210/MMRDX cells remains to be identified but may prove a novel one, highly specific for this class of mdr-active anthracyclines.

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Selected References

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  1. Coley H. M., Twentyman P. R., Workman P. 9-Alkyl, morpholinyl anthracyclines in the circumvention of multidrug resistance. Eur J Cancer. 1990;26(6):665–667. doi: 10.1016/0277-5379(90)90112-7. [DOI] [PubMed] [Google Scholar]
  2. Endicott J. A., Ling V. The biochemistry of P-glycoprotein-mediated multidrug resistance. Annu Rev Biochem. 1989;58:137–171. doi: 10.1146/annurev.bi.58.070189.001033. [DOI] [PubMed] [Google Scholar]
  3. Grandi M., Pezzoni G., Ballinari D., Capolongo L., Suarato A., Bargiotti A., Faiardi D., Spreafico F. Novel anthracycline analogs. Cancer Treat Rev. 1990 Sep;17(2-3):133–138. doi: 10.1016/0305-7372(90)90037-g. [DOI] [PubMed] [Google Scholar]
  4. Gros P., Ben Neriah Y. B., Croop J. M., Housman D. E. Isolation and expression of a complementary DNA that confers multidrug resistance. Nature. 1986 Oct 23;323(6090):728–731. doi: 10.1038/323728a0. [DOI] [PubMed] [Google Scholar]
  5. Habig W. H., Jakoby W. B. Assays for differentiation of glutathione S-transferases. Methods Enzymol. 1981;77:398–405. doi: 10.1016/s0076-6879(81)77053-8. [DOI] [PubMed] [Google Scholar]
  6. Hayes J. D., Wolf C. R. Molecular mechanisms of drug resistance. Biochem J. 1990 Dec 1;272(2):281–295. doi: 10.1042/bj2720281. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Hilton J., Sartorelli A. C. Induction of phenobarbital of microsomal mixed oxidase enzymes in regenerating rat liver. J Biol Chem. 1970 Aug 25;245(16):4187–4192. [PubMed] [Google Scholar]
  8. Jesson M. I., Johnston J. B., Robotham E., Begleiter A. Characterization of the DNA-DNA cross-linking activity of 3'-(3-cyano-4-morpholinyl)-3'-deaminoadriamycin. Cancer Res. 1989 Dec 15;49(24 Pt 1):7031–7036. [PubMed] [Google Scholar]
  9. Lau D. H., Lewis A. D., Sikic B. I. Association of DNA cross-linking with potentiation of the morpholino derivative of doxorubicin by human liver microsomes. J Natl Cancer Inst. 1989 Jul 5;81(13):1034–1038. doi: 10.1093/jnci/81.13.1034. [DOI] [PubMed] [Google Scholar]
  10. Lewis A. D., Lau D. H., Durán G. E., Wolf C. R., Sikic B. I. Role of cytochrome P-450 from the human CYP3A gene family in the potentiation of morpholino doxorubicin by human liver microsomes. Cancer Res. 1992 Aug 15;52(16):4379–4384. [PubMed] [Google Scholar]
  11. Norman M. R., Thompson E. B. Characterization of a glucocorticoid-sensitive human lymphoid cell line. Cancer Res. 1977 Oct;37(10):3785–3791. [PubMed] [Google Scholar]
  12. Ripamonti M., Pezzoni G., Pesenti E., Pastori A., Farao M., Bargiotti A., Suarato A., Spreafico F., Grandi M. In vivo anti-tumour activity of FCE 23762, a methoxymorpholinyl derivative of doxorubicin active on doxorubicin-resistant tumour cells. Br J Cancer. 1992 May;65(5):703–707. doi: 10.1038/bjc.1992.148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Roninson I. B. The role of the MDR1 (P-glycoprotein) gene in multidrug resistance in vitro and in vivo. Biochem Pharmacol. 1992 Jan 9;43(1):95–102. doi: 10.1016/0006-2952(92)90666-7. [DOI] [PubMed] [Google Scholar]
  14. Tietze F. Enzymic method for quantitative determination of nanogram amounts of total and oxidized glutathione: applications to mammalian blood and other tissues. Anal Biochem. 1969 Mar;27(3):502–522. doi: 10.1016/0003-2697(69)90064-5. [DOI] [PubMed] [Google Scholar]
  15. Watanabe M., Komeshima N., Nakajima S., Tsuruo T. MX2, a morpholino anthracycline, as a new antitumor agent against drug-sensitive and multidrug-resistant human and murine tumor cells. Cancer Res. 1988 Dec 1;48(23):6653–6657. [PubMed] [Google Scholar]
  16. Westendorf J., Groth G., Steinheider G., Marquardt H. Formation of DNA-adducts and induction of DNA-crosslinks and chromosomal aberrations by the new potent anthracycline antitumor antibiotics: morpholinodaunomycin, cyanomorpholinodaunomycin and cyanomorpholinoadriamycin. Cell Biol Toxicol. 1985 Jan;1(2):87–101. doi: 10.1007/BF00717794. [DOI] [PubMed] [Google Scholar]

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