Antitumor activity of yunnanmycin. A novel pyrimidine nucleoside antibiotic.
Explore the source record for details and available documents.
Animals↗
Biomedical subjects
Y S Zhen
Publications and source records attributed to Y S Zhen.
Mechanism of Formation of Novel Covalent Drug·DNA Interstrand Cross-Links and Monoadducts by Enediyne Antitumor Antibiotics
The potent enediyne antitumor antibiotic C1027 has been previously reported to induce novel DNA interstrand cross-links and drug monoadducts under anaerobic conditions [Xu et al. (1997) J. Am. Chem. Soc. 119, 1133-1134]. In the present study, we explored the mechanism of formation of these anaerobic DNA lesions. We found that, similar to the aerobic reaction, the diradical species of the activated drug initiates anaerobic DNA damage by abstracting hydrogen atoms from the C4', C1', and C5' positions of the A1, A2, and A3 nucleotides, respectively, in the most preferred 5'GTTA1T/5'ATA2A3C binding sequence. It is proposed that the newly generated deoxyribosyl radicals, which cannot undergo oxidation, likely add back onto the nearby unsaturated ring system of the postactivated enediyne core, inducing the formation of interstrand cross-links, connecting either A1 to A2 or A1 to A3, or drug monoadducts mainly on A2 or A3. Comparative studies with other enediynes, such as neocarzinostatin and calicheamicin gamma1I under similar reaction conditions indicate that the anaerobic reaction process is a kinetically competitive one, depending on the proximity of the drug unsaturated ring system or dioxygen to the sugar radicals and their quenching by other hydrogen sources such as solvent or thiols. It was found that C1027 mainly generates interstrand cross-links, whereas most of the anaerobic lesions produced by neocarzinostatin are drug monoadducts. Calicheamicin gamma1I was found to be less efficient in producing both lesions. The anaerobic DNA lesions induced by enediyne antitumor antibiotics may have important implications for their potent cytotoxicity in the central regions of large tumors, where relative anaerobic conditions prevail.
Journal Article↗
A study on the growth curve of and maximum profit from layer-type cockerel chicks.
1. 2900 commercial layer-type cockerel chicks were reared on the floor from 1-day-old to 9 weeks of age. 2. The growth curve of the cockerel chicks was [formula see text] 3. The feeding costs (US$) of layer-type cockerel chicks were described by the equation Y = a + bx + cx2 = 0.0657 - 0.0091x + 0.0069x2. 4. When the layer-type cockerel chicks' marketing price was US$0.82 per kg. (6.8 Renminbi per kg), the optimum marketing age for maximum profit margin was 5.9 weeks (41 to 42 d).
Animal Husbandry↗
[Antitumor activity of yungumycin].
Yungumycin, produced by a Streptomyces strain which was isolated from a soil sample collected in Guanping Nature Conservation Zone, Yunnan Province, China, has been verified to be identical with gougerotin. Determined by clonogenic assay, the IC50 of yungumycin to KB cells was found to be 1 microgram.ml-1. By spermatogonial assay, the activity of yungumycin was very close to that of 5-FU and MTX. Administered by i.p. route, yungumycin showed moderate inhibition against colon carcinoma 26 in mice. However, yungumycin by oral administration exerted highly inhibitory effects on both colon carcinoma 26 and sarcoma 180 (solid tumor) in mice and the inhibition rates reached 85% and 83%, respectively, at tolerable dose. Compared at equitoxic dose of 1/6 LD50, the inhibitory effect of yungumycin (15 mg.kg-1) on sarcoma 180 was similar to that of 5-FU (40 mg.kg-1), showing 72% and 70% tumor inhibition, respectively. Initially, gougerotin was reported as an antibacterial antibiotic without mentioning its antitumor activity. The present studies demonstrate that yungumycin (gougerotin), by oral administration, may be useful in cancer chemotherapy.
Animals↗
A single binding mode of activated enediyne C1027 generates two types of double-strand DNA lesions: deuterium isotope-induced shuttling between adjacent nucleotide target sites.
It has been previously reported that the potent enediyne antitumor antibiotic C1027 chromophore produces in DNA restriction fragments double-strand lesions at the sequence GTTA1T/ATA2A3C (damage positions are numbered), involving A1 and A3 [Xu, Y.-j., Zhen, Y.-s., & Goldberg, I. H. (1994) Biochemistry 33, 5947-5954]. Using oligodeoxynucleotide substrates, an additional double-strand lesion has been found within this sequence to involve A1 and A2. The lesions, which include strand breaks and abasic sites, are due to hydrogen atom abstraction from C4' at A1 and from C5'at A3 or C1' at A2 by the diradical species of activated drug. Lesions at A2 or A3 are always part of double-strand lesions. The drug radical center involved in attack at A2 or A3 is readily quenched by solvent methanol so as to produce a single-strand lesion at A1. By using methanol containing carbon-bound deuterium, there is a substantial isotope effect on the quenching reaction, resulting in enhanced double-strand lesion formation. In the absence of methanol, almost all damage at A1 belongs to double-strand lesions. There is a considerable flexibility of the drug radical attacking A2 or A3, such that the presence of deuterium at C1' of A2 results in substantial shuttling of the attack to the C5' of the neighboring nucleotide A3. These data strongly suggest the presence of a single mode of binding of activated drug but one which permits the drug diradical center attacking A2 or A3 to have considerable leeway in target selection. Quantitative affinity cleavage binding analysis is consistent with this proposal.
Aminoglycosides↗
Induction of apoptosis by enediyne antitumor antibiotic C1027 in HL-60 human promyelocytic leukemia cells.
C1027, a new macromolecular antitumor antibiotic with an enediyne chromophore, displays extremely potent cytotoxicity against cancer cells. HL-60 human promyelocytic leukemia cells treated with C1027 (0.1-10 nM) for 2 hours resulted in morphological changes, including Hoechst 33342-stained condensed nuclei, condensation of nuclear chromatin, and nuclear fragmentation. Agarose gel electrophoresis of C1027-treated HL-60 cells showed a typical ladder-like pattern of DNA fragments. In addition, the apoptotic DNA peak of propidium iodide-stained nuclei was revealed by flow cytometry. Treatment of HL-60 cells with C1027 (5 nM) induced apoptosis in up to 79% of the cells. The results suggest that C1027 may exert antitumor activity by triggering apoptosis.
Aminoglycosides↗
[Relationship between the molecular composition of C1027, a new macromolecular antibiotic with enediyne chromophore, and its antitumor activity].
The molecule of C1027, an antitumor antibiotic with extremely potent cytotoxicity against cultured cancer cells, is composed of an enediyne chromophore and an apoprotein of 10.5 kDa. These two parts of the molecule, connecting each other through non-covalent binding, can be dissociated and reconstituted. As determined by clonogenic assay, the chromophore served as the active part of the molecule, displaying potent cytotoxicity similar to that of intact C1027. The activity of free chromophore decreased more rapidly than that of intact C1027, indicating that apoprotein played a role in protecting the chromophore from inactivation. By incubating together in phosphate buffer, the chromophore and apoprotein were reconstituted to form an intact C1027. The ratio of chromophore and apoprotein remained 1 : 1 in the reconstituted molecule, even though extra amount of chromophore was added. The optimal condition for the reconstitution was pH 7.0, at 20 degrees C for 12 h. When the disulfide bond of the apoprotein was reduced by DTT, the activity of C1027 decreased more rapidly. C1027 was digested by pronase and the produced fragments of various molecular weights were examined by capillary electrophoresis. The cytotoxicity of 3-5 kDa fragment approximated that of intact C1027 and its IC50 value was 0.07 fmol.L-1. The results indicate that the intactness of the apoprotein is not indispensable for stabilizing the chromophore and a smaller molecule of 3-5 kDa consisting of a peptide fragment and a chromophore may retain full C1027 activity.
Aminoglycosides↗
[Effect of the conjugate composed of a human monoclonal antibody and pingyangmycin on mammary cancer].
To avoid or reduce the induction of human anti-mouse antibody reaction, it is important to use human antibody for the preparation of therapeutic immunoconjugate. CM1, a human monoclonal antibody directed against mammary cancer, was linked to pingyangmycin (PYM), an antitumor antibiotic identical to bleomycin A5 currently in clinical use, employing Dextran T-40 as an intermediate agent. As determined by clonogenic assay with mammary cancer CAMA cells, the IC50 values for CM1-PYM conjugate and free PYM were 0.35 mumol.L-1 and 4.0 mumol.L-1, respectively. Mammary cancer CAMA was transplanted sc in nude mice. Peritumoral injection of CM1-PYM conjugate at doses of 1.25 mg.kg-1 and 2.5 mg.kg-1 inhibited the growth of CAMA xenograft by 86% and 95% (P < 0.01), whereas the injection of equivalent doses of free PYM inhibited CAMA xenograft by 49% and 58% (P < 0.05), respectively. CM1-PYM conjugate showed remarkable suppression on CAMA xenograft and the inhibitory effect of CM1-PYM conjugate was much higher than that of free PYM. By histo-pathological examination, no toxic changes were found in the heart, lung, liver, intestines, kidney, spleen and bone marrow of the CM1-PYM- or PYM-treated animals. These results suggest that local administration of the immunoconjugate composed of a human monoclonal antibody and pingyangmycin is highly effective and the conjugate may be useful in therapy for human breast cancer.
Animals↗
[Minocycline potentiates the antimetastatic effect of boanmycin].
Boanmycin (bleomycin A6, BAM) was found to markedly inhibit the spontaneous pulmonary metastasis of Lewis carcinoma in mice. Compared at equitoxic doses (1/9 LD50), BAM was more effective than mitomycin. Minocycline (MNO) at 5 mg.kg-1 showed no inhibition on the growth of sc transplanted Lewis primary tumor; however, it markedly potentiated the antimetastatic effect of BAM. Treated with BAM (5 mg.kg-1) alone, the number of total metastatic foci and that of large foci (> 2 mm in diameter) in the lung were suppressed by 67% and 85%, respectively. When BAM was used in combination with MNO, the number of those foci was further reduced by 88% and 100%, respectively. By NAG enzyme assay, MNO was not cytotoxic and showed no synergism with BAM against PG cells, a cell line derived from a highly metastatic human giant cell carcinoma of the lung. Determined by ELISA with a monoclonal antibody, the expression of type IV collagenase in PG cells was remarkably inhibited by MNO. The intracellular free Ca2+ level in PG cells was reduced from 76.7 nmol.L-1 to 42.2 nmol.L-1 by MNO treatment. The study suggests that the combination of boanmycin and minocycline may be useful for control of tumor metastasis and the inhibition of type IV collagenase expression may be involved in the mechanism of minocycline potentiation.
Animals↗
C1027 chromophore, a potent new enediyne antitumor antibiotic, induces sequence-specific double-strand DNA cleavage.
C1027, a new macromolecular antitumor antibiotic produced by a Streptomyces strain, shows highly potent cytotoxicity to cultured cancer cells and marked DNA cleaving ability. The structure of its chromophore, responsible for most of the biological activities of the antibiotic, was recently determined and found to contain a nine-membered enediyne. In contrast to other enediyne antibiotics, such as neocarzinostatin, calicheamicin, esperamicin, and recently found kedarcidin, C1027 damages duplex DNA even in the absence of thiols. The DNA damage caused by C1027 includes double-strand breaks, single-strand breaks, and abasic sites. Experiments with plasmid DNA and 32P-end-labeled restriction fragments demonstrated that the chromophore, extracted from the protein-containing holoantibiotic, interacts in the DNA minor groove and cleaves double-helical DNA with a remarkable sequence-selectivity causing direct double-strand breaks. The double-strand cleavage sites, occurring predominantly at CTTTT/AAAAG, ATAAT/ATTAT, CTTTA/TAAAG, CTCTT/AAGAG, and especially GTTAT/ATAAC, consist of five nucleotide sequences with a two-nucleotide 3'-stagger of the cleaved residues (cutting sites are underlined). The chemical structures of the damaged residues at the GTTAT/ATAAC cleavage site suggest a model in which a C1027-induced double-strand break results from abstraction, by a single molecule of the diradical form of the chromophore, of a C4' hydrogen atom from the A residue of GTTAT and a C5' hydrogen atom from the A of ATAAC on the opposite strand. Single-strand breaks, which are mainly produced at adenylate and thymidylate residues, appear to be separate events presumably resulting from different binding modes of the drug to DNA.(ABSTRACT TRUNCATED AT 250 WORDS)
Alkynes↗
Novel nucleoside transport inhibitors of natural origin.
Explore the source record for details and available documents.
Animals↗
[A fungus-derived novel nucleoside transport inhibitor potentiates the activity of antitumor drugs].
Antibiotic C3368-B (CB), identified as 3,9-dihydroxy-1-methoxy-7-methylanthraquinone, is produced by a fungus strain, Chrysosporium verrucosum Tubaki, isolated from a soil sample collected from Antarctica. CB was found to be a highly-active nucleoside transport inhibitor. By radiolabelled nucleoside assay, CB was shown to markedly inhibit thymidine and uridine transport in Ehrlich carcinoma cells, with IC50 values of 7.5 and 9.6 mumol.L-1 respectively. CB showed fairly low cytotoxicity to tumor cells. The IC50 values for epidermoid cancer KB cells and hepatoma BEL-7402 cells in clonogenic assay was 77 and 69 mumol.L-1. At relatively noncytotoxic concentrations, CB markedly enhanced the cytotoxicity of methotrexate, 5-fluorouracil, mitomycin C against KB cells and BEL-7402 cells. CB was also found to partly reverse the multi-drug resistance to vincristine and actinomycin D in leukemia L1210/MDR cells. The IC50 values were reduced by 4.9-fold (1.75 to 0.36 mumol.L-1) for vincristine and 3.3-fold (0.39 to 0.12 mumol.L-1) for actinomycin D. These results suggest that CB, as a newly-found nucleoside transport inhibitor, may be potentially useful in cancer chemotherapy.
Animals↗
[Anticancer immunoconjugates: current status and prospects].
Explore the source record for details and available documents.
Animals↗
[Experimental studies on therapeutic effect of rat monoclonal antibody-bleomycin A6 conjugate against human colorectal cancer].
Bleomycin A6 (A6), a single component of bleomycin complex, is highly active against human colon and cecum cancer cells in vitro and xenografts in nude mice. R19, a rat monoclonal antibody against human cecum cancer Hce-8693 cells, was linked to A6. R19-A6 conjugate retained complete activity of McAb R19 and 10% activity of A6. As determined by clonogenic assay with human cecum cancer Hce-8693 cells for 1 hour exposure. The 50% inhibitory concentration (IC50) values for R19-A6, A6 and M3-A6 (conjugate of irrelevant Mc-A6) were 0.019, 1.05 and 1.00 mumol/L, respectively. The effect of the conjugate R19-A6 was 55-fold stronger than that of free A6 and 53-fold than irrelevant conjugate M3-A6. Clonogenic assay with human colon cancer HT-29 cells showed that the IC50 values were 0.078 mumol/L and 4.0 mumol/L for R19-A6 and free A6, respectively. The cytotoxicity to Hce-8693 and HT-29 cells was markedly blocked by unconjugated McAb R19 but not by irrelevant McAb MARK-3. The R19-A6 conjugate exerted 90% inhibition on the growth of cecum cancer Hce-8693 xenografts in nude mice, whereas equivalent doses of free A6, R19 plus A6 mixture and M3-A6 showed 52%, 34% and 48% inhibition, respectively. Histopathological examination showed no toxic changes in the heart, lung, liver, kidney and bone marrow in the R19-A6 conjugate treated animals.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
[Antitumor effect of the immunoconjugate composed of antibiotic C1027 and Fab fragment from a monoclonal antibody directed against human hepatoma].
Antibiotic C1027, a macromolecular peptide with highly potent cytotoxicity to cultured cancer cells, was conjugated to monoclonal antibody 3A5 and its Fab fragment separately using SPDP as the linker agent. McAb 3A5, identified as IgG1, was directed against human hepatoma BEL-7402 cells. By ELISA, McAb 3A5 and the Fab fragment were strongly reactive with hepatoma cells and weakly reactive with KB cells. Determined by clonogenic assay against hepatoma BEL-7402 cells, the IC50 values for McAb-C1027, Fab-C1027 and C1027 were 4.2 x 10(-14), 8.6 x 10(-16) and 6.5 x 10(-16) mol.L-1, respectively. Fab-C1027 was 49-fold more potent than McAb-C1027 in cytotoxicity. Moreover, Fab-C1027 was 160-fold more potent in cytotoxicity to hepatoma cells than to KB cells, indicating selective cytotoxicity of Fab-C1027 conjugate to the target cells. Therapeutic effect of the conjugate was evaluated with hepatoma BEL-7402 xenograft in nude mice. After subcutaneous transplantation of the tumor, treatment started on day 3, iv, with equivalent dose of C1027, 0.1 mg.kg-1 x 6. Fab-C1027 and free C1027 inhibited tumor growth by 85% and 59%, respectively. Fab-C1027 conjugate showed more marked antitumor effect in vivo than free C1027.
Aminoglycosides↗
[Antitumor activity of new antitumor antibiotic C1027 and its monoclonal antibody assembled conjugate].
C1027, a new macromolecular peptide antitumor antibiotic produced by Streptomyces globisporus C1027, shows extremely potent cytotoxicity to cultured cancer cells. The antibiotic is composed of an apoprotein and a chromophore and the latter serves as the active part of the compound. C1027 was separated into apoprotein and chromophore by methanol extraction and the separated parts can be reconstituted to form the active C1027 molecule in phosphate buffer. For determination of the specificity of C1027 reconstitution, the apoprotein was incubated with epirubicin and the chromophore was incubated with H16, a McAb directed against hepatoma cells. Notably, the reconstitution of C1027 occurred neither between apoprotein and epirubicin nor between chromophore and IgG molecule. In addition, bovine serum albumin showed no competition with C1027 apoprotein in binding to the chromophore. Various methods for linking C1027 to McAb were studied and two kinds of immunoconjugates have been prepared: (1) direct conjugate was made by linking C1027 to McAb, using SPDP as a linker agent, (2) assembled conjugate was made by linking and reconstitution, including 3 steps. Firstly, the chromophore was extracted with methanol and stored at -70 degrees C in drak. Secondly, the apoprotein was conjugated to McAb by SPDP and finally the extracted chromophore was added to the McAb-apoprotein conjugate. Determined by clonogenic assay, the IC50 values for hepatoma cells were 42 pmol/L, and 5.5 pmol/L, respectively, for direct conjugate and assembled conjugate. The IC50 value of M3-C1027 assembled conjugate prepared by linking the irrelevant McAb M3 to C1027 was 1,400 pmol/L.(ABSTRACT TRUNCATED AT 250 WORDS)
Aminoglycosides↗
Azidothymidine and dipyridamole as biochemical response modifiers: synergism with methotrexate and 5-fluorouracil in human colon and pancreatic carcinoma cells.
Azidothymidine (AZT), inhibiting thymidine kinase (EC 2.7.1.21) (Weber, G. et al., Cancer Commun. 2:129-133, 1990) and dipyridamole, inhibiting nucleoside transport (Zhen, Y.-s. et al., Cancer Res. 43:1616-1619, 1983) exert blocking action on the activities of salvage pathways of nucleotide biosynthesis. Determined by clonogenic assay in human colon cancer HT-29 cells, the cell survivals for AZT, 10 microM, dipyridamole, 5 microM, and methotrexate (MTX), 0.025 microM, were 90, 82, and 62%, respectively; while the combinations of AZT + MTX, dipyridamole + MTX and AZT + dipyridamole + MTX, reduced survivals to 36, 4.3, and 0.7%. AZT or dipyridamole was synergistic with MTX, whereas AZT plus dipyridamole showed an even more marked potentiation of MTX activity. The survivals for 5-fluorouracil (5-FU), 0.5 microM, alone, AZT + 5-FU, dipyridamole + 5-FU, and AZT + dipyridamole + 5-FU were 86, 47, 29 and 5.1%, respectively. Similar results were observed in human pancreatic carcinoma BxPC-3 and PANC-1 cells. AZT markedly enhanced the inhibitory effect of dipyridamole in reversing the thymidine-hypoxanthine rescue from MTX cytotoxicity. AZT inhibited [14C]thymidine incorporation into DNA in HT-29 cells and strongly enhanced the effect of dipyridamole. The results indicate that combinations composed of AZT, dipyridamole, and antimetabolites, such as MTX and 5-FU, are potentially effective in the chemotherapy of human neoplasias.
Adenocarcinoma↗
[Experimental studies on the antitumor activity of monoclonal antibody--bleomycin A6 conjugate against human liver cancer].
Bleomycin A6 (A6), a single component of bleomycin complex, is highly active against human liver cancer cells in vitro and xenografts in nude mice. A6 was conjugated to monoclonal antibody H111 directed against human hepatoma BEL - 7402 cells, using Dextran T40 as an intermediate. The conjugate consisted of a coupling molar ratio of 1:264 for H111 and A6, and retained 6.3% of A6 activity. As determined by clonogenic assay with hepatoma BEL - 7402 cells exposed to the agents for 1 h, the IC90 values for H111 - A6 conjugate, free A6 and M3 - A6 conjugate (an irrelevant conjugate) were 0.17 mu mol/L, 17 mu mol/L and 7 mu mol/L respectively. The cytotoxicity of Hill - A6 conjugate to target cells was markedly blocked by unconjugated H111 but not by irrelevant monoclonal antibody M3. The H111 - A6 conjugate exhibited 78% inhibition on the growth of hepatoma BEL - 7402 xenografts in nude mice, whereas the equivalent doses of free A6, M3 - A6 conjugate and H111 plus A6 mixture showed approximately 30% inhibition. Histopathological examination showed no toxic changes in the liver, lung, kidney and bone marrow in the H111 - A6 conjugate--treated animals. These results suggest that the conjugate of monoclonal antibody and bleomycin A6 exhibits specific cytotoxicity to target liver cancer cells and the conjugate is highly effective against liver cancer xenografts in nude mice with more marked tumor inhibition than free A6 at comparable dose levels.
Animals↗