aclarubicin and Leukemia-L5178

Aclacinomycin is a member of naturally occurring anthracyclines having three sugar moieties in the molecule. It showed antitumour activity on various mouse and rat tumours. Combination therapy with AraC etc. gave remarkable clinical results on acute myeloid leukaemia. Aclacinomycin strongly inhibits RNA synthesis of the tumour cells. It has lower cardiac toxicity than adriamycin and no mutagenicity. THP-Adriamycin is a derivative of adriamycin designed from the structure of baumycins. It showed stronger effects than adriamycin in inhibiting many mouse tumours such as L1210 and P388 leukaemia, B16 melanoma and colon 38 adenocarcinoma. THP-Adriamycin is rapidly taken up by both adriamycin-sensitive and resistant leukaemic cells. Its level of cardiac toxicity is as low as that of aclacinomycin. Ditrisarubicins are new naturally occurring anthracyclines isolated from Streptomyces having six sugar moieties in the molecule. Ditrisarubicin has a potent cytostatic and antitumour activities on adriamycin resistant mouse leukaemia. Its binding constant to DNA is extremely high compared with other anthracyclines.

Topics: Aclarubicin; Animals; Anthracyclines; Antibiotics, Antineoplastic; Cricetinae; Doxorubicin; Heart; Leukemia L1210; Leukemia L5178; Mice; Myocardium; Naphthacenes; Rats; RNA

DBA/2 mice implanted i.p. with an aclarubicin (ACR)-resistant subline of L5178Y cells survived 4- to 5-fold longer than those with the parental cells; and animals with the Adriamycin- or bleomycin-resistant subline displayed an intermediate survival period. The i.p. treatment of mice with cyclophosphamide markedly enhanced i.p. growth of the ACR-resistant cells, suggesting that a certain host defense mechanism participates in the lower transplantability. In vitro, the ACR-resistant subline showed much higher sensitivity to natural killer cells. The i.p. pretreatment with anti-asialo-GM1 antibody markedly reduced the mean survival period of mice implanted i.p. with the ACR-resistant cells, suggesting that natural killer cells play an important role in the defense against transplantation of the ACR-resistant cells.

Topics: Aclarubicin; Animals; Antigen-Antibody Reactions; Cyclophosphamide; Cytotoxicity, Immunologic; Drug Resistance; G(M1) Ganglioside; Glycosphingolipids; Immunity, Cellular; Killer Cells, Natural; Leukemia L5178; Leukemia, Experimental; Macrophages; Mice; Mice, Inbred DBA; Naphthacenes; Neoplasm Transplantation

An aclacinomycin A-resistant subline of mouse lymphoblastoma L5178Y cells was isolated by successive treatment of tumor-bearing mice with the antibiotic. IC50 (50% growth inhibition) in culture was observed at a drug concentration of 0.22 micrograms/ml, which was ca. 11 times higher than IC50 for the parental cells. The resistant cell line exhibited cross resistance to mitomycin C, actinomycin D, macromomycin, auromomycin, vinblastine, cytochalasin B, and other anthracyclines: daunorubicin, adriamycin, 4'-O-tetrahydropyranyladriamycin, baumycins A1 and A2, aclacinomycins B and Y, MA144-S1, 1-deoxypyrromycin, cinerubin A, musettamcyin, and pyrromycin. The 1-deoxy group of anthracyclines showed higher degree of cross resistance than the 1-hydroxy group. No significant cross resistance was found with bleomycin A2, neothramycin and blasticidin S. The resistance to aclacinomycin A and cross resistance to adriamycin were also demonstrated by the method of uridine incorporation. The accumulation or retention studies with [3H]adriamycin revealed that the resistance may be due to decreased uptake and increased efflux of the antibiotic in the resistant cells.

Topics: Aclarubicin; Animals; Antibiotics, Antineoplastic; Cell Line; Doxorubicin; Drug Resistance; Kinetics; Leukemia L5178; Leukemia, Experimental; Mice; Mice, Inbred Strains; Naphthacenes; RNA, Neoplasm