Activity of boanmycin against colorectal cancer.
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Animals↗
Biomedical subjects
Y S Zhen
Publications and source records attributed to Y S Zhen.
[Inhibitory effect of boanmycin on the growth of colon carcinoma 26 and hepatic metastasis in mice].
AIM: To investigate the therapeutic effect of boanmycin (BAM, bleomycin A6) on colon carcinoma 26 and its hepatic metastasis in mice. METHODS: A series of models including subcutaneous transplantation, orthotopic transplantation in cecum subserosa, intra-hepatic transplantation of tumor, and intrasplenic transplantation of tumor accompanied with hepatic metastases were employed. In addition, LEICA Q 500IW image analysis system was used to determine the area of metastatic lesions in the liver in histopathological sections. RESULTS: BAM at 5 mg.kg-1 and 2.5 mg.kg-1 inhibited the growth of subcutaneous tumors by 78.7% and 61.9%, and the orthotopic tumors by 99.4% and 90.0%; and the intra-hepatic tumors by 86.9% and 75.7%, respectively. Determined by the numbers of metastatic nodules, BAM at 10 mg.kg-1 and 5 mg.kg-1 inhibited hepatic metastases from intra-splenic transplantation by 97.6% and 56.8%; and evaluated by image analysis of metastatic lesions, by 100% and 63.3%, respectively. CONCLUSION: Boanmycin is highly effective in a panel of models including the subcutaneous, orthotopic, intra-hepatic transplanted tumors, and hepatic metastases of murine colon carcinoma 26.
Animals↗
Synergistic effects of geldanamycin and antitumor drugs.
AIM: To study the effect of geldanamycin (GDM) on cell-cycle of human hepatoma BEL-7402 cells and the antitumor activity of cisplatin and mitomycin C in combination with GDM in vitro and in vivo. METHODS: MTT assay was used to determine the growth inhibition of hepatoma BEL-7402 cells. Cell cycle was analyzed by flow cytometry. Transplantable murine hepatoma 22 model was used to evaluate the antitumor activity of drugs in vivo. RESULTS: The IC50 value of GDM for hepatoma BEL-7402 cells by MTT assay was found to be 0.28 mumol.L-1. At concentrations of 0.1, 1.0, and 10 mumol.L-1, GDM reduced the proportion of S phase and induced G2/M arrest in BEL-7402 cells. At relatively low cytotoxic concentration, 0.1 or 0.2 mumol.L-1, GDM markedly potentiated the cytotoxicity of a series of chemotherapeutic agents including cisplatin, mitomycin C, adriamycin and cytarabine against BEL-7402 cells. The inhibition of tumor growth by cisplatin and mitomycin C was also enhanced in transplantable hepatoma 22-bearing mice when these agents were administered in combination with GDM 0.38 mg.kg-1. The synergistic effects were very significant with CDI < 0.7. CONCLUSION: These results suggest that GDM, as a biochemical modulator targeting Hsp90 function, may be potentially useful in cancer chemotherapy.
Animals↗
[Advances in antitumor activity of the hsp90 inhibitor geldanamycin].
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Animals↗
[Rhein induces apoptosis in cancer cells and shows synergy with mitomycin].
AIM: To study the apoptosis-inducing and growth-inhibitory effect of rhein, an herb-derived compound, and its combination with mitomycin C (MMC) on cultured tumor cells. METHODS: MTT assays were used to determine the inhibition of proliferation by drugs in several tumor cell lines. Nucleoside transport and DNA synthesis inhibition were determined by [3H] thymidine transport and incorporation assays. Flow cytometry, electrophoresis on agarose gels and morphological assessment were applied to analyze the apoptotic changes. RESULTS: The IC50 values of nucleoside transport was 19.1 micrograms.mL-1 and that of the DNA synthesis inhibited by rhein was 27.4 micrograms.mL-1. In MTT assay the IC50 values of rhein for KB, hepatoma BEL-7402 and mammary carcinoma MCF-7 cells were 11.5 micrograms.mL-1, 14.0 micrograms.mL-1 and 18.4 micrograms.mL-1 respectively. Synergistic effect of rhein and MMC was found in all the three cell lines. As found, rhein induced apoptosis in KB cells, and the increase of apoptotic cells reached 71.0% at 96 h. The combination of rhein and MMC enhanced the induction of apoptosis significantly. CONCLUSION: These results suggest that rhein, as a biochemical modulator, might be potentially useful in cancer chemotherapy.
Anthraquinones↗
[Antitumor effect of lidamycin-containing monoclonal antibody immunoconjugate with downsized-molecule].
OBJECTIVE: To develop a novel monoclonal antibody (mAb) immunoconjugate with downsized-molecule and highly potent antitumor effects. METHODS: The mAb conjugate was prepared by linking lidamycin (LDM), an antitumor antibiotic with extremely potent cytotoxicity, to mAb Fab' fragment. The molecular weight of Fab'-LDM was determined by non-reduced SDS-PAGE. The immunoreactivity of Fab'-LDM conjugate with cancer cells was detected by ELISA. The antitumor activity of the conjugate was determined by MTT assay, clonogenic assay, and animal model of transplantable colon carcinoma 26' (C26) in mice. RESULTS: The relative molecular mass of Fab'-LDM conjugate was approximately 65,000, suggesting a molar ratio of 1:1 between Fab' fragment and LDM in the conjugate. Fab'-LDM was reactive with hepatoma BEL-7402 and colon carcinoma 26 cells, but not reactive with KB cells. The cytotoxicity of Fab'-LDM conjugate to BEL-7402 cells, the antigen relevant cancer cells, was 13-fold more potent than that of free LDM, while the cytotoxicity of Fab'-LDM conjugate against C26 cells was 5.5-fold more potent than that of free LDM. However, the cytotoxicity of Fab'-LDM conjugate to KB cells, the antigen irrelevant cells, was similar to that of free LDM. Given by 3 intravenous injections, on day 1, 4 and 7, Fab'-LDM conjugate at doses of 0.05 mg/kg, 0.1 mg/kg and 0.2 mg/kg markedly suppressed the growth of colon carcinoma 26 in mice by 80%, 92% and 94%, respectively, whereas free LDM at 0.1 mg/kg suppressed the growth by 77%. The survival time of tumor-bearing mice was also increased by Fab'-LDM conjugate treatment. Fab'-LDM conjugate was more effective than equivalent unconjugated LDM (P < 0.01). CONCLUSIONS: The immunoconjugate composed of LDM and Fab' fragment that is characterized by downsized-molecule shows remarkable effectiveness against tumor growth.
Aminoglycosides↗
Antitumor components from an actinomycete strain 6011W.
Three bioactive compounds that inhibited nucleoside transport were isolated from the cultured broth of Streptoverticillium sp. 6011W. The structures of those compounds were characterized as cinnamamide, N-(tetrahydro-2-oxo-3-thienyl)-acetamide and benzamide, respectively. They all inhibited radiolabeled thymidine transport into Ehrlich carcinoma cells, with IC50 values of 30.4, 97.2 and 85.4 microM, respectively. When administered i.p., cinnamamide not only inhibited the growth of transplanted tumors but also reduced the number of lung metastases in mice bearing Lewis lung carcinoma. The results suggest that nucleoside transport inhibition assay is a valuable model to search for antitumor agents of natural origin.
Actinomycetales↗
Antitumor activity of yunnanmycin. A novel pyrimidine nucleoside antibiotic.
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Animals↗
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↗
[A monoclonal antibody directed against an enediyne antitumor antibiotic and its preliminary application].
C1027, composed of an enediyne chromophore and an apoprotein of 110 amino acid residues, is a new highly potent macromolecular antitumor antibiotic. In order to prepare monoclonal antibodies (McAb) against C1027 by hybridoma technique, natural C1027 was inactivated by ultraviolet and coupled with human serum albumin, then immunized BALB/c mice. After cell fusion and screening by ELISA, a hybridoma secreting anti-C1027 McAb designated as F9 was obtained. McAb F9 specifically reacted with C1027 as determined by immunoblot assay. No obvious difference was observed between the reactivity of McAb F9 to natural C1027 and that of McAb F9 to ultraviolet inactivated C1027. This result indicates that the ultraviolet-sensitive chromophore of C1027 may not participate in the epitope for McAb F9. The isotype of F9 is IgG1 and its affinity constant was found to be (2.2 +/- 0.47) x 10(7) L.mol-1 according to Beatty's method. By clonogenic assay, McAb F9 neither affected the cytotoxicity of C1027 to KB cells nor blocked the activity of the chromophore. McAb F9 also specifically reacted with the recombinant truncated C1027 apoprotein in which 16 amino acid residues at the C terminus were deleted. This study suggests that F9 is a valuable McAb for the research of C1027 apoprotein engineering, C1027 related immunoconjugates and screening of new macromolecular antitumor substances with homology to the protein part of C1027.
Aminoglycosides↗
[Antitumor activity of the clavam peptide antibiotic G0069A].
Antibiotic G0069A, produced by a Streptomyces strain isolated from a soil sample collected in Yunnan Province, China, has been verified as a clavam peptide. Determined by MTT assay, G0069A showed highly potent cytotoxicity to cancer cells with multidrug resistance. The IC50 values of G0069A to KB and KB/VCR cells were 0.60 and 0.46 mumol.L-1, and to MCF-7 and MCF-7/ADM cells were 1.4 and 1.2 mumol.L-1, respectively. G0069A displayed equally potent cytotoxicity to the parent cell lines and their resistant sublines. When administered by i.v. or i.p. route at tolerable doses, G0069A exhibited markedly inhibitory effect on the growth of sarcoma 180 and hepatoma 22 in mice. At dose level of 3 mg.kg-1, i.v., x3, sarcoma 180 and hepatoma 22 were suppressed by 87%(P < 0.01) and 72%(P < 0.01), respectively. The results indicate that G0069A is a beta-lactam antibiotic showing antitumor activity.
Animals↗
[Use of monoclonal antibody-pinyangmycin conjugate in experimental regional targeting therapy of tumor].
McAb 3A5, a rat monoclonal antibody, was linked to pingyangmycin (PYM), an antitumor antibiotic identical to bleomycin A5 currently in clinical use, employing Dextran T-40 as an intermediate agent. The 3A5-PYM conjugate retained complete immunoreactivity of McAb 3A5. Determined by clonogenic assay with colon cancer HT-29 cells, the IC50 values for 3A5-PYM conjugate and free PYM were 0.6 mumol.L-1 and 10.2 mumol.L-1, respectively. Hepatoma H22 ascites was transplanted into the peritoneal or thoracic cavity of mice. On the next day, 3A5-PYM or PYM, were injected into the cavity. Therapeutic effect was evaluated on the survival time of mice. For intraperitoneal tumor, the ILS(%) values were 238% for 3A5-PYM and 40% for PYM. For intrapleural tumor, the ILS(%) values were 384% for 3A5-PYM and 66% for PYM. Murine hepatoma H22 was transplanted s.c. into mice and 3A5-PYM conjugate or free PYM were injected peritumorally. As determined by antimicrobial assay, the administration of 3A5-PYM showed higher concentration and longer retention time in the tumor than that of free PYM. Tumor fragments of human colon cancer HT-29 were transplanted s.c. into nude mice. Then 3A5-PYM or PYM was injected i.v., i.p. or pt (peritumorally) 3 days after inoculation, twice a week, with a total of 7 injections. Tumor growth inhibition was evaluated 4 weeks later. The inhibition rates on the growth of colon cancer xenografts were as follows: (1) for i.v. route, 58% by PYM, 79% by 3A5-PYM; (2) for i.p. route, 52% by PYM, 61% by 3A5-PYM; and (3) for pt route, 73% by PYM, 96% by 3A5-PYM. These results indicate that 3A5-PYM conjugate is highly effective against targeted human cancer xenograft and mouse tumor when administered peritumorlly or intracavitarily.
Animals↗
[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↗