About one third of patients with various malignant diseases were found to have extractable amounts of DNA in their plasma whereas no DNA could be detected in normal controls. Using the test established by one of us (M. B.), which is based on decreased strand stability of cancer cell DNA, we have found that several plasma DNA originate from cancer cells.
The high template in vitro activity of native DNA from cancerous mammalian and plant tissues, compared to DNA from healthy tissues, enabled us to select substances which selectively inhibit cancer DNA synthesis. Among them, alstonine, serpentine, semper-virine and flavopereirine, all alkaloids which belong to the β -carboline class, distinguish cancer DNA from healthy tissue DNA and inhibit DNA in vitro synthesis when native DNA from different cancerous tissues or cells is used as template. They have practically no effect on DNA from healthy tissues. The inhibitory effect of alkaloids is due to their capacity to form an ‘alkaloid-cancer DNA’ complex which has been characterized by use of the Sephadex column. Evidence is presented showing that these alkaloids inhibit the initiation of DNA synthesis but not chain elongation. The stimulating action caused by carcinogens during cancer DNA in vitro synthesis may be prevented and reversed by alkaloids. Furthermore, the stimulating action of steroids during in vitro synthesis of hormone target tissue DNA might be neutralized by alkaloids. However, at relatively high doses, steroids reversibly compete with alkaloids for binding sites on breast cancer DNA. This is not observed with DNA from nonhormone target tissues.
Alstonine, serpentine and sempervirine, when used at appropriate concentrations cure a relatively important proportion of BALB/C mice inoculated with transplantable YC8 lymphoma ascites cells, as well as Swiss mice bearing Ehrlich ascites carcinoma cells. The development of some solid tumors was only partially prevented. However, when one alkaloid was administered in association with either 5-FU, daunorubicin, 1-(2-chloroethyl) nitrosourea (CCNU) or cyclophospahmide (CP) to mice bearing either ascites carcinoma cells or solid tumors, a high rate of cure was obtained without toxicity. The role of the three alkaloids in the curing of mice and prevention of carcinogenesis is discussed.
The chemicals 9,10-dimethylbenzanthracene (DMBA), ethionine, daunorubicin, actinomycin D, l-(2-chloroethyl-1)-nitrosourea (CCNU), steroids, croton oil and dimethylsulfoxide (DMSO) were used in order to correlate their effect on the in vitro synthesis of normal and cancer DNA, on DNA strand separation and on accelerated in vivo multiplication of cancer cells. All of the compounds tested strongly stimulate the synthesis of cancer DNA in vitro catalyzed by DNA-dependent DNA polymerase I and measured as an acid-precipitable labeled product. Under the same conditions, the synthesis of DNA originating from healthy tissues is only slightly enhanced, except in the case of croton oil and DMSO. These substances are almost equally active on cancer and normal DNA. Although both cancer and normal DNA contain a large amount of double-stranded regions, the extent of DNA strand separation measured by the increase in UV absorbance (hyperchromicity) in the presence of each compound tested is much higher for all cancer DNA than for corresponding normal DNA. In contrast, DMSO and croton oil do not appear to distinguish cancer DNA from normal DNA. Additive and differential effects of various compounds on cancer DNA strand separation can be observed. Small doses of DMBA and CCNU stimulate the multiplication of Ehrlich ascites tumor cells in vivo in mice. There is thus a possible correlation between DNA strand separation, DNA synthesis, multiplication and differentiation of cancer cells in the presence of the above compunds, which is different from the response of normal cells to these compounds.
In a mutant of Escherichia coli resistant to showdomycin, both the 50S and 30S ribosomal subunits contain RNA species in which the purine concentration greatly exceeds that of pyrimidines. The same is true for total rapidly-labeled RNA. The modified ribosomal RNA hybridizes poorly with homologous DNA, which is apparently unchanged in base composition. Acrylamide gel electrophoresis of mutant ribosomal proteins shows a highly altered protein pattern for both ribosomal subunits, although the activity of these ribosomes is not decreased.In bacteria, the ribosomes play an important role in the translation mechanism for protein synthesis (1) and constitute the primary site of action of several antibiotics (2-6). Each ribosomal subunit, 50S and 30S, has a specific functional role essentially linked to a group of proteins (7,8), whose synthesis is under genetic control (9-12). Structural genes for ribosomal proteins may be the loci conferring sensitivity (12, 13) to and dependence (14) on antibiotics. Thus, it has been shown that certain antibiotics provoke the alteration exclusively of a single protein in 50S ribosomal subunits, while others affect a single protein of the 30S subunits. In a mutant of E. coli resistant to erythromycin or lincomycin, a single protein associated with 50S ribosomal subunits seems to be altered (4,15), while in the case of resistance to streptomycin (11,14) and spectinomycin (5) a single protein of the 30S subunits is functionally modified. The biological activity of ribosomes seems to depend on the presence of the correct ribosomal proteins while the ribosomal RNA is needed for the assembly of these proteins (16).We have previously shown that showdomycin, a naturally occurring "nucleoside" (17, 18), rapidly provokes in E. coli (19,20) Ribosomal RNA (23S, 16S, and 5S) was isolated by the phenol method and separated as described (20). After alkaline hydrolysis (KOH, 0.5 N, 18 hr at 370C), the nucleotides were analyzed using a Dowex 1 X 2 column, -200-400 mesh (20). For base-ratio analysis, 1 mg of each type of RNA was used.
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