A new antibiotic, ayamycin A2, has shown antitumor activity against HeLa cells in vitro and Ehlrich ascites carcinoma in vivo1,2).
About 20 streptomyces antibiotics have the quinoid structure and several of this group are known to have anti-tumor activity such as cinerubin3), luteomycin4), mitomycin C5), and ractinomycin A6).
Since ayamycin A2 also belongs to this group, the present study was made to test its effectiveness on a number of experimental animal tumor systems. The tumor spectrum employed consisted of 30 solid tumors, 2 ascites tumors and 1 virus leukemia.
Among many microbiological products exhibiting inhibition against experimental animal tumors, there are those of macromolecular nature, such as Shear’s polysaccharide1), actinogan2), melanomycin3), carcinomycin4), carzinocidin5), marinamycin6), kunomycin7) and others. Similar to these macromolecular antitumor antibiotics, A114, C776, D92, D180, D284, D440, D847, Sgf334, A216 and A280 substances have been isolated from the culture filtrates of the selected ten Streptomyces species in this laboratory.
The present paper concerns the preliminary chemical and biological studies performed with these 10 substances, including some detailed experiments on A216 and A280 substances.
The antiviral effect of N′, N′-anhydrobis (β-hydroxyethyl) biguanide (ABOB)1) as evaluated in this laboratory against the PR8 strain of influenza virus both in embryonated eggs and in mice was not far different from the control. However, our later studies2) proved its effectiveness against Sendai virus in tissue culture in a reproducible manner. Meanwhile, the clinical usefulness of the compound was reported by several authors. Then the situation directed us to find more potent biguanide derivatives as anti-influenza agent. Along this line, ten biguanide derivatives were prepared. For the primary screening of these compounds, both the Sendai virus growth in HeLa cell cultures and the PR8 virus growth in the Maitland type tissue cultures of chorioallantoic membrane were used. As described above, the former system was adequately sensitive to detect the effect of ABOB and the latter has been known to be most sensitive in detecting various agents of antiviral activity, such as antimetabolites, antibodies or the inhibitors of animal origin3).
Of those compounds tested, N′-isobutylbiguanide and N′-benzylbiguanide were found more effective than ABOB at least in these tissue culture system. Moreover, toxicity test performed in mice suggested higher chemotherapeutic index of these compounds, particularly of the former. The studies to be reported in this article are chiefly concerned with the in vitro activity and the toxicity in mice of 10 compounds so far tested. The animal experiments with these in vitro effective compounds will be reported in the next paper4).
In the course of searching new antibiotics produced by actinomycetes using Ehrlich ascites carcinoma as a testing tool, a new antitumor antibiotic designated cervicarcin was isolated in a crystalline form from the culture filtrate of Streptomyces ogaensis which will be reported in a forthcoming paper.
The isolation and physical and chemical properties as well as some of the biological properties are described in this paper.
Primocarcin discovered in our laboratory is a new antitumor antibiotic produced by Nocardia fukayae. The taxonomic studies, the physico-chemical properties and the chemical structure of this substance were reported in previous papers1,2,3). in this paper, antitumor effect of primocarcin against transplantable mouse tumors, particularly ascitic forms of Ehrlich carcinoma and Sarcoma 180, and the toxicity of promocarcin are presented.
Rifamycin SV (formerly rifomycin SV) is a new antibiotic discovered by Sensi et al1). It inhibits the growth of Gram-positive bacteria including Mycobacterium tuberculosis2). It was effective against experimental infections with Gram-positive bacteria3), and it had a very low toxicity4). It was found recently that this antibiotic is effective against infections in humans5–10).
It was reported that Staphylococcus aureus (209 P) rapidly developed resistance to this antibiotic and various strains resistant to other antibiotics were as equally susceptible to rifamycin SV as did that susceptible stain2). However, it is not known how develop strains resistant to other antibiotics resistance to rifamycin SV and, on the contrary, how behave rifamycin-resistant stains in developing resistances to other antibiotics. Resistance pattern to rifamycin SV is still unknown. The present paper deals with these subjects using Staphylococcus aureus 209 P as the test strain.
Several workers1–6) have reported that leucomycin, an antibiotic isolated by Hata and his colleagues7–11) in 1953 from a culture filtrate of Streptomyces kitasatoensis Hata, has a broad antibacterial spectrum which includes gram-positive and some gram-negative bacteria, spirochaetes, rickettsiae and some larger viruses. Leucomycin also exhibits a clinical efficacy for various kinds of infectious diseases caused by those microorganisms. Recently, Abe and others12) demonstrated that leucomycin is a mixture composed of at least six biologically active components, A1, A2, B1, B2, B3 and B4, which were separated by paper chromatographic and electrophoretic methods. The fraction A1 ranked first in antimicrobial activity.
In view of the scarcity of fundamental and systematic data on in vitro antibacterial activity of leucomycin, the authors examined this agent, especially the A1 fraction, in respect to the antibacterial activity against a variety of pathogenic bacteria, especially erythromycin-resistant staphylococci. The influence of a change in pH of a culture medium and the addition of whole blood or its components to a medium on the antibacterial activity of leucomycin and A1 fraction were also investigated.
The results obtained from these studies were compared with activities of similar antibiotics, erythromycin and oleandomycin.
It is a general trend that in most hospitals where antibiotics are used extensively, infections caused by antibiotic-resistant bacteria, especially staphylococci, including those of hospital-acquired, have been encountered with increasing frequency. Eisenberg et al1). stated that for several years following their introduction into clinical usage, erythromycin, chloramphenicol, and the tetracyclines were all effective in the treatment of penicillinresistant staphylococcal infections encountered in their hospitals, including those that were considered to be hospital-acquired, but by the midsummer of 1958, the effectiveness of erythromycin and the tetracyclines had declined to the point that only about 50% and 30–25% of the staphylococci, respectively, isolated from lesions were susceptible to these agents, and only chloramphenicol continued to show a relatively high degree of effectiveness, 80–85%.
In a previous study, the authors reported on the in vitro antibacterial activity of leucomycin-free base and the A1 fraction (one of the biologically active components of leucomycin), pointing out that these drugs possess a strong antibacterial activity on antibiotic-resistant staphylococci. In view of a serious problem on antibiotic-sesistant staphylococcal infections and also of the effectiveness of leucomycin against erythromycinresistant staphylococci, as shown by Eisenberg et al. in clinical and laboratory examinations and also by the present authors in in vitro studies, an attempt was made to extend the studies on drug resistance or susceptibility of staphylococci to erythromycin and leucomycin in respects to (1) comparison of the in vitro acquired resistance of sensitive staphylococcal strains against the two antibiotics and cross resistance among them, and (2) comparison of the degree of growth of the sensitive and resistant strains, including those isolated from patients and those influenced by the addition of antibiotics to their growth environment. Through these experiments the authors expected to clarify the existence of any possible difference in antibacterial activity between the two antibiotics, though some informations available on these antibiotics showed that they have close similarities in physical, chemical and biological properties.