Criteria for Selection of New Analogs of Antitumor Antibiotics

  • A. Goldin
Part of the Recent Results in Cancer Research / Fortschritte der Krebsforschung / Progrès dans les recherches sur le cancer book series (RECENTCANCER, volume 63)


A highly difficult area in the application of preclinical methodology involves the selection and development of new analogs of known antitumor agents for clinical trial. There are a considerable number of analogs of alkylating agents, purine and pyrimidine antagonists, folic acid antagonists, dimethane sulfonates, benzimidazols, antibiotics of a number of subcategories, and other classes of drugs which have demonstrable activity in antitumor test models but which have remained “dormant” with respect to development, pending any experimental observations that would provide a basis for further interest. The problems involved in the selection of new analogs of antitumor antibiotics are not dissimilar from those involved in the selection of new analogs in general. It is important to examine the preclinical criteria that may be employed in an attempt to identify analogs of antitumor antibiotics that are worthy of further development for the clinic. In general, standard preclinical testing methodologies may be employed to provide data as a guide for selection. Overall, if a new analog of a known antitumor antibiotic is to justify interest, the analog must be demonstrated to possess either quantitative or qualitative superiority over the parent compound in pharmacologic, toxicologic, immunologic, tumor cytotoxic, or other biologic properties that are therapeutically favourable. In such a determination, it is important to focus specific attention on the characteristics that are limiting for the parent antitumor antibiotic in clinical use. Various preclinical criteria for selection of new antitumor antibiotics for clinical use will be discussed below.


Lewis Lung Carcinoma Cytosine Arabinoside Antitumor Antibiotic Anthracycline Derivative Arabinosyl Cytosine 
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  1. 1.
    Bonadonna, G., Brusamolino, E., Valagussa, P., Rossi, A., Brugnatelli, L., Brambilla, C., Delena, M., Tancini, G., Bajetta, E., Musumeci, R., Veronesi, U.: Combination chemotherapy as an adjuvant treatment in operable breast cancer. N. Engl. J. Med. 294; 405–410 (1976).PubMedCrossRefGoogle Scholar
  2. 2.
    Bonmasser, E., Bonmassar, A., Vadlamudi, S., Goldin, A.: Immunological alteration of leukemic cells in vivo after treatment with an antitumor drug. Proc. Natl. Acad. Sci. USA 66, 1089–1095 (1970).CrossRefGoogle Scholar
  3. 3.
    Bradner, W. T., Imanishi, H., Hirth, R. S., Wodinsky, I.: Antitumor activity and toxicity of BU-2231-A, a new bleomycin analogue. Proc. Am. Assoc. Cancer Res. 18, 35 (1977).Google Scholar
  4. 4.
    Casazza, A. M., Isetta, A. M., Giuliani, F., DI Marco, A.: Immunodepressive activity of daunomycin and adriamycin. In: Adriamycin Review. Staquet, M. et al (eds.) Ghent, Belgium: European Press Medikon 1975, pp. 123–131.Google Scholar
  5. 5.
    Detre, S. I., Davies, A. J. S., Connors, T. A.: New models for cancer chemotherapy. Cancer Chemother. Rep. Pt. II, 5 (1), 133–145 (1975).Google Scholar
  6. 6.
    Di Marco, A., Casazza, A. M. Pratesi, G.: Antitumor activity of 4-demethoxydaunorubicin (NSC 256,439) administered Orally. Cancer Treat. Rep. 61, (5), 893–894 (1977).PubMedGoogle Scholar
  7. 7.
    Garibjanian, B. T., Johnson, R. K., Kline, I., Vadlamudi, S., Gang, M., Venditti, J. M., Goldin, A.: Comparison of 5-fluorouracil and ftorafur. II. Therapeutic Response and Development of Resistance in Murine Tumors. Cancer Treat. Rep. 60 (9), 1347–1361 (1976).PubMedGoogle Scholar
  8. 8.
    Goldin, A., Johnson, R. K.: Evaluation of actinomycins in experimental systems. Cancer Chemother. Rep. Pt. I, 58, (1), 63–77 (1974).Google Scholar
  9. 9.
    Goldin, A., Johnson, R. K.: Experimental Grounds for Combination Chemotherapy. Excerpta Medica International Congress Series No. 353, Proc. XI Int. Cancer Cong. Florence 1974, Vol. V, pp. 308–313.Google Scholar
  10. 10.
    Goldin, A., Johnson, R. K.: Experimental tumor activity of adriamycin (NSC 123127). Cancer Chemother. Rep. Pt. III, 6, 137–145 (1975).Google Scholar
  11. 11.
    Goldin, A., Johnson, R. K.: Antitumor effect of adriamycin in comparison with related drugs, and in combination chemotherapy. In: Adriamycin Review. Staquet, M. et al (eds.) Ghent, Belgium: European Press Medikon 1975 pp. 37–54.Google Scholar
  12. 12.
    Goldin, A., Johnson, R. K.: Adriamycin activity in experimental tumors. In: Ergebnisse der Adriamycin—Therapie. Ghione, M., Fetzer, J., Maier, H. (eds.): Berlin: Springer-Verlag 1975, pp. 3–13.CrossRefGoogle Scholar
  13. 13.
    Goldin, A., Johnson, R. K.: Resistance to antitumor agents. EORTC Monograph Series (In Press) (1977).Google Scholar
  14. 14.
    Humphreys, S. R., Thomas, L. B., Chirigos, M. A., Goldin, A., Crawford, E. J., Friedkin, M.: Use of dihydrofolate reductase as a biochemical index of chemotherapy. Nature 195, 453–455 (1962).PubMedCrossRefGoogle Scholar
  15. 15.
    Humphreys, S. R., Glynn, J. P., Goldin, A.: Suppression of the homograft response by pretreatment with antitumor agents. Transplantation 1, 65 69 (1963).Google Scholar
  16. 16.
    Jaenke, R. S.: An anthracycline antibiotic-induced cardiomyopathy in rabbits. Lab. Invest. 30, 292–304 (1974).PubMedGoogle Scholar
  17. 17.
    Jaenke, R. S., Colo., St. U: personal communication.Google Scholar
  18. 18.
    Johnson, R. K., Ovejera, A. A., Goldin, A.: Activity of anthracyclines against an adriamycin (NSC-123127)—resistant subline of P-388 leukemia with special emphasis on cinerubin A (NSC-18334). Cancer Treat. Rep. 60 (1), 99–102 (1976).PubMedGoogle Scholar
  19. 19.
    Laster, W. R., Jr.: Ridgway osteogenic sarcoma—A promising laboratory model for special therapeutic trials against an advanced—staged, drug-sensitive animal tumor system. Cancer Chemother. Rep. Pt. II, 5 (1), 151–168 (1975).Google Scholar
  20. 20.
    Lenaz, L., Page, J. A.: Cardiotoxicity of adriamycin and related anthracyclines. Cancer Treat. Rev. 3(3), 111–120(1976).PubMedCrossRefGoogle Scholar
  21. 21.
    Myers, C. E., Mcguire, W., Young, R.: Adriamycin: amelioration of toxicity by α-tocopherol. Cancer Treat. Rep. 60 (7), 961 962(1976).Google Scholar
  22. 22.
    Nicolin, A., Vadlamudi, S., Goldin, A.: Antigenicity of L1210 leukemic sublines induced by drugs. Cancer Res. 32, 653–657 (1972).PubMedGoogle Scholar
  23. 23.
    Ohno, R., Nishikawa, H., Kawashima, K., Uetani, T., Hirano, M., Miura, M., Yamada, K.: Lack of immunosuppressive effect of bleomycin on the primary response of mice to sheep red blood cells. Gann 62, 267(1971).Google Scholar
  24. 24.
    Sandberg, J. S., Howsden, F. L., Di Marco, A., Goldin, A.: Comparison of the antileukemic effect in mice of adriamycin (NSC-123127) with daunomycin (NSC-82151). Cancer Chemother. Rep. Pt. 1, 54(1), 1–7(1970).Google Scholar
  25. 25.
    Schabel, F. M., Jr.: Nitrosoureas: A review of experimental antitumor activity. Cancer Chemother. Rep. 60 (6), 665–698 (1976).Google Scholar
  26. 26.
    Schabel, F. M., Jr., Laster, W. R., Jr., Trader, M. W., Witt, M. H.: Combination chemotherapy with cyclophosphamide plus melphalan against leukemia L1210. Proc. Am. Assoc. Cancer Res. 16, 24(1975).Google Scholar
  27. 27.
    Skipper, H. E., Schabel, F. M., Jr.: Quantitative and Cytokinetic Studies in Experimental Tumor Models. Cancer Medicine. Holland, J. F., Frei, E. (eds.): Phila.: Lea & Febiger 1973, Vol. III, pp. 629–650.Google Scholar
  28. 28.
    Skipper, H. E., Schabel, F. M., Jr. Trader, M. W., Laster, W. R., Jr.: Response to therapy of spontaneous, first passage, and long passage lines of AK leukemia. Cancer Chemother. Rep. 55, 345–366(1969).Google Scholar
  29. 29.
    Skipper, H.E., Hutchison, D. J., Schabel, F.M., Jr., Schmidt, L.H., Goldin, A., Brockman, R.W., Venditti, J. M., Wodinsky, I.: A quick reference chart on cross resistance between anticancer agents. Cancer Chemother. Rep. Pt. I, 56 (4), 493–498 (1972).Google Scholar
  30. 30.
    Umezawa, H.: Development and mechanism of action of bleomycin. In: New Drug Seminar on Bleomycin. Soper, W. Gott, A.: Natl. Cancer Inst. 1974.Google Scholar
  31. 31.
    Venditti, J. M.: Relevance of transplantable animal tumor systems to the selectiqn of new agents for clinical trial. In: Pharmacological Basis of Cancer Chemotherapy. Univ. of Texas System Cancer Center, Baltimore: The Williams & Wilkins Co. 1975, pp. 245–270.Google Scholar
  32. 32.
    Yamaki, H., Tanaka, N., Umezawa, H.: Effects of several tumor-inhibitory antibiotics on immunological response. J. Antibiot. (Tokyo) 22, 315 (1969).Google Scholar
  33. 33.
    Young, D. M.: Pathologic effects of adriamycin (NSC-123127) in experimental systems. Cancer Chemother. Rep. Pt. III, 6 (2), 159–175 (1975).Google Scholar
  34. 34.
    Zbinden, G., Brandle, E.: Toxicologic screening of daunorubicin (NSC-82151) adriamycin (NSC-123127), and their derivatives in rats. Cancer Chemother. Rep. Pt. I, 59 (4), 707–715 (1975).Google Scholar

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© Springer-Verlag Berlin · Heidelberg 1978

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  • A. Goldin

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