172 



DESCRIPTIONS OF ANTIBIOTICS 



proceeding to a 2:3 ratio in the eluent. Complete 

 separation is made by preparative paper chroma- 

 tography (N-dibutyl ether-tetrachloroethane-10 

 per cent sodium o-cresotinate) (62, 101). 



Chemical and physical properties: These mixtures 

 contain actinomycins I(Ai , Bi , Xufi), II(Aii , 

 Bii), III(Ain , Bin), IV(Aiv , Biv , Div , X,), and 

 V (Av , Bv , Xo) in varying proportions (See 

 Table 38). "J mixture" has been identified with 

 "X mixture" (83), but precise data have not been 

 published. The A, B, and X mixtures also contain 

 a number of other actinomycins, not yet char- 

 acterized, in trace amounts. Physical and chemical 

 properties of the major actinomycins I to V are 

 given in Tal)le 40. The infrared spectrum of IV is 

 given in reference 36, and infrared data on II and 

 III are given in reference 101. Amino acid content 

 of the peptide moieties of actinomycins I to V is 

 given in Table 39 (24, 77). For information on the 

 various mixtures see references 1 , 4 (A mixture); 

 13, 19, 62, 82 (B) ; 32 (D) ; 6, 9, 12, 17 (J) ; 25, 28, 37, 

 44, 46, 62 (X). 



Biological activity: Actinomycins I to V are 

 active on gram-positive bacteria, less active on 

 mycobacteria, and inactive on fungi (102). Some 

 typical activities of components I, IV, and V are 

 given in Table 41. Actinomycins II and III were 

 about half as active as IV in vitro (86). Tested in 

 mice against Gardner lymphosarcoma (6C3HED) 

 (ascitic form), actinomycins I and V had much less 

 activity than IV, and II and III had equal or 

 better activity than IV (60, 86). Actinomycin IV 

 has been reported active on the following tumors: 

 Crocker sarcoma 180 (50), malignant melanoma 

 S91, mammary adenocarcinoma, myeloid and 

 lymphoid leukemia (53), Ehrlich carcinoma (as- 

 citic form), Krebs 2 ascitic carcinoma (54), Ridge- 

 way osteogenic sarcoma, carcinoma 1025 (90), ME 

 1 melanoma (human amelanotic), MFSl myxo- 

 fibrosarcoma, KB (Eagle human carcinoma), 

 P1534 mouse lymphatic leukemia (88), RC mam- 

 mary carcinoma (91), mammary adenocarcinomas 

 C 755 and C 3HBA, thymoma (solid), and the 

 ascites form of an ovarian carcinoma (70). Infor- 

 mation on the various mixtures is given in refer- 

 ences 26 and 55. Treatment of actinomycins with 

 methanolic sodium hydroxide opens the lactone 

 rings in the polypeptide chains. The resulting 

 compounds are called actinomycinic acids. The 

 actinomycinic acid of actinomycin S3 has no anti- 

 bacterial activity but some antitumor activity 

 (108). 



Toxicity: LDjo (mice) subcutaneously (60): 

 actinomycin I, > 8 mg per kg; actinomycin IV, 1.1 



Table 41 



Biological activity of actinomycin components I, 



IV, and V against four test organisms (60) 



mg per kg; actinomycin V, 0.35 mg per kg. LD50 

 (mice) intraperitoneally (86): actinomycin II, 6 

 mg per kg; actinomycin III, 1.5 mg per kg. Actin- 

 omycin I had much less toxicity than IV and V, as 

 measured by splenic atrophy (60). Actinomycin 

 IV (D) had a teratogenic effect on the rat foetus 

 at 10 jug per mother rat (4). It was also intensely 

 irritating to skin and subcutaneous tissue. In 

 human beings, side effects included depletion of 

 bone marrow, stomatitis, pigmentation of the skin, 

 and gastrointestinal disturbances (93). Other 

 toxicity studies with actinomycin IV in animals 

 (70) and normal and neoplastic tissue cell cultures 

 (68) have been reported. 



Utilization: Used experimentally in the treat- 

 ment of certain neoplastic diseases (69, 92, 93). 



Actinomycin mixtures {C and AA-A(') Containing 

 Acfinotnycins IV, VI, and VII 



Produced by: Strcptomyces chrysomallus (20), 

 <S. griseus (84), S. chrysomallus var. fumigatus 

 (99), and Slreptomyccs sp. (5, 23, 28, 64, 85, 87). 



Synonym: Antibiotic HBF 386 ("C mixture"). 



Method of extraction: Ground dried mycelium 

 extracted with benzene. Broth extracted with 

 butjd acetate. Broth-extract concentrated in 

 vacuo, residue dissolved in benzene-extract from 

 mycelium, and the whole chromatographed on 

 alumina. Eluted with ethyl acetate; eluate con- 

 centrated. Addition of carbon disulfide to con- 

 centrate gives i)recipitate of crude ' C mixture." 

 Washed with ethyl acetate-carbon disulfide 

 (1:2) and carbon disulfide. Recrystallized from 

 ethyl acetate, ether, methanol, or ethanol. Sepa- 

 ration of major components by countercurrent 

 distribution (5 per cent Na p-xylol sulfonate- 

 mothyl l)utyl ether-n-dil)utyl ether) (16, 23) or 

 by chromatography on alumina (33). 



Chemical and physical properties: "C mixture" 

 contains three major components, actinomycins 

 IV(Ci), VI(C2), and VII(C3), and a number of 



