YAKHAK HOEJI (약학회지)

The Pharmaceutical Society of Korea (대한약학회)
권호 표지

Distribution of Acriflavine in Rats Following Intramuscular Administration of a Mixture of Acriflavine and Guanosine, a Potential Antitumor Agent

신규 항암성 화합물 아크리플라빈과 구아노신 복합체를 흰쥐에 근육주사시 아크리플라빈의 체내분포

  • Song, Suk-Gil (National Research Laboratory (NRL), College of Pharmacy, Chungbuk National University) ;
  • Chung, Youn-Bok (National Research Laboratory (NRL), College of Pharmacy, Chungbuk National University)
  • 송석길 (충북대학교 약학대학 국가지정연구실) ;
  • 정연복 (충북대학교 약학대학 국가지정연구실)
  • Published : 2006.02.01
Download PDF
⟨ Previous Next ⟩

Abstract

A 1 : 1 mixture of acriflavine (ACF; CAS 8063-24-9) and guanosine is currently being evaluated as a possible antitumor agent in preclinical studies. Guanosine is known to potentiate the anticancer activity of some compounds. However, the distributions of trypaflavine (TRF) or proflavine (PRF) have not been investigated in mammals. We, therefore, investigated the distribution of TRF and PRF after i.m. administration of the combination mixture (ACF and guanosine) at a dose of 30 mg/kg ACF in rats. to analyze TRF and PRF levels in biological samples, we used an HPLC-based method. The calibration curves for TRF and PRF in the samples were linear over the concenration range of $0.05{\sim}200\;{\mu}g/ml$. The intra- and inter-day assay accuracies of this method were within ${\pm}15\%$ of norminal values and the precision did not exceed $15\%$ of relative standard diviation. The lower limits of quantitation were 50 ng/ml for both TRF and PRF. The distribution of TRF or PRF was determined by 48 h after i.m. administration of the combination mixture at a dose of 30 mg/kg ACF. TRF and PRF were distributed as the following order; kidney>lung>liver>small intestine>muscle. Of the various tissues, TRF and PRF were mainly distributed to the kidney and lung. The concentrations of TRF or PRF in the tissues 24 h after i.m. administration decreased to undetectable levels. The concentrations of TRF or PRF in the blood cells were comparable to those for the plasma. However, the concentrations of TRF or PRF in the both plasma and blood cells 12 h after i.m. administration were not detected. The number of the platelets in the 1 ml of the blood was calculated to be $0.183{\times}10^8/ml$ of blood. The PRF concentration in platelets was higher than that of TRF at initial times after i.m. administration of the combination mixture. However, both the TRF and PRF concentrations in the plateles 24 h after i.m. administration of the combination mixture were below the quantifiable limit. In conclusion, the concentrations of TRF or PRF in the various tissues, plasma, blood cells, and plateles decreased to undetectable levels 24 h after i.m. administration of the combination mixture at a dose of 30 mg/kg ACF.

Keywords

References

  1. Macadam, R. F. and Williamson, J. : Drug effects on the fine structure of Trypanosoma rhodesienes: acriflvine, ethidium and antrycide. Annal. Tropic. Med. Parasitol. 68, 291 (1974)
  2. Canellakis, E. S. and Chen, T.-K. : Relationship of biochemical drug effects to their antitumor activity-I. Biochem. Pharmacol. 28, 1971 (1979) https://doi.org/10.1016/0006-2952(79)90653-1
  3. Boss, S., Gothoskar, B. P. and Ranadive, K. J. : Studies of biological macromolecules: II. Effect of acriflavine exposure on the synthesis of macromolecules in liver cells in vivo. Experimental Cell Res. 42, 89 (1966) https://doi.org/10.1016/0014-4827(66)90323-5
  4. Borisova, O. F., Shchyolkna, N. K. and Tchurikov, N. A. : Relative stability of AT and GC pairs in pararell DNA duple x formed by a natural sepuence. FEBS Letter 322, 304 (1993) https://doi.org/10.1016/0014-5793(93)81591-M
  5. Wadler, S. and Wiernik, P. H. : Partial reversal of doxorubicin resistance by forskolin and 1,9-dideoxyforskolin in murine sacoma S180 variants. Cancer Res. 48, 539 (1988)
  6. Chakraborty, N. G., Bose, S. R. and Joy Chowdhury, J. R. : Acriflavine-induced surface changes in three tumor cell types and differential sensitivity to lectins. Tumori. 70, 127 (1984)
  7. Chakraborty, N. G., Boss, S. R. and Joy Chowdhury, J. R. : Enhancement of immunogenisity of tumor cells by modification of cell surface with acridine dyes. Indian J. Experi. Biol. 18, 927 (1980)
  8. Chakraborty, N. G. and Boss, S. R. : Protective immunity by chemically modified tumor cell antigens extracted by 3 M KCl. Neoplasma 34, 427 (1987)
  9. Roth, D., London, M. and Manjon, M. : Binding specificity and affinity of acriflavine for nucleic acids. Stain Tech. 42, 125 (1967) https://doi.org/10.3109/10520296709114994
  10. Ferey, L., Herlin, P., Marnay, J., Mandard, A.-M., Catania, R., Lubet, P., Lande, R. and Bloyet, D. : Pararosanilline or acriflavine-schiff staining of epoxy embedded tissue periodic acid oxidation in ethanol: a method suitable for morphometric and fluorometric analysis of glycogen. Stain Tech. 61, 107 (1986) https://doi.org/10.3109/10520298609110717
  11. Wuthrich, C., Deranleau, D. A., Eubler, D. and Luscher, E. F. : Human blood platelet secretions: optical multichannel analyser meeeeasurements using acriflavine as a release indicator. Biochemistry 23, 1224 (1984) https://doi.org/10.1021/bi00301a031
  12. Hannun, Y. A. and Bell, R. M. : Aminoacridines, Potent inhibitors of protein kinase C. J. Biol. Chem. 263, 5124 (1988)
  13. Kimura, M., Okabayashi, I. and Kato, A. : Acridine derivatives. III. Preparation and antitumor activity of the novel acridinylsubstituted uracils. Chem. Pharm. Bull. 37, 697 (1989) https://doi.org/10.1248/cpb.37.697
  14. Scholtissek, C. and Becht, H. : Action of acridine on RNA and protein synthesis and on active transport in chick embryo cells. Biochim. Biophys. Acta 123, 585 (1966) https://doi.org/10.1016/0005-2787(66)90225-5
  15. Iigo, M. and Hoshi, A. : Effect of guanosine on antitumor activity of fluoinated pyrimidines against P388 leukemia. Cancer Chemotherapy Pharmacol. 13, 86 (1984)
  16. Iigo, M. and Hoshi, A. : Influence of molar ratio on the combination effect of 5-fluorouracil with guanosine 5'-monophosphate on P388 and L1210 leukemias. Eur. J. Cancer Clin. Oncol 20, 411 (1984) https://doi.org/10.1016/0277-5379(84)90089-0
  17. Iigo, M. and Hoshi, A. : Potentiation of antitumor activity of 5- fluoro-2'-deoxyuridine by guanosine 5'-monophosphate. J. Pharm. Dyn. 7, 67 (1984) https://doi.org/10.1248/bpb1978.7.67
  18. Iigo, M., Kuretani, K. and Hoshi, A. : Relationship between antitumor effect and metabolites of 5-fluorouracil in combinationtreatment with 5-fluorouracil in ascites sarcoma 180 tumoor system. Cancer Res. 43, 67 (1983)
  19. Iigo, M., Miwa, M., Ishtsuka, H. and Nitta, K. : Potentiation of the chemotherqaputic action of 5'-deoxy-fluorouridine in combination with guanosine and related compounds. Cancer Chemother. Pharmacol. 19, 61 (1987) https://doi.org/10.1007/BF00296258
  20. Iigo, M., Nakajima, Y, Kuretani. K. and Hoshi, A. : Potentiation of the chemotheraputic effect of 5-fluorouacil by combination with guanosine 5'-monophosphate. Gann 74, 291 (1983)
  21. Osswald H. and Yussef, M. : Potentiation of thee chemotherapeutic action of 5-fluorouracil by combination with cytidine or guanosine on HRS-Sacoma. J. Cancer Res. Clin.Oncol 93, 241 (1979) https://doi.org/10.1007/BF00964579
  22. Santelli, G. and Valeriote, F. : In vivo enhancement of 5- fluorouracil cytotoxicity to AKR leukemia cells by thymidine in mice. J. Natl., Cancer Inst. 61, 843 (1978)
  23. Goodman, M. G. Weigle, W. O. : Manifold amplification of in vivo immunity in normal and immunodeficient mice by ribonucleosides derivatized at C8 of guanine. Proc. Natl. Acad. Sci. USA 80, 3452 (1983)
  24. Choi, S. Y., Kim, M. H., Lee, S. H., Jung, Y. S., Baik, E. J., Ryu, C. K. and Moon, C. H. : Antiplatelet action of 2-bromo-3-(3,5- tert-butyl-4-hydroxylpheneyl)-1,4-naph- thalenedione (TPN2). J. Applied Pharmacol. 7, 227 (1999)