Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:5.99.1.2 (topoisomerase)
 9,166 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We synthesized a potent new antitumor podophyllotoxin derivative (4beta-aminoalkyl-4'-O-demethyl-4-desoxypodophyllotoxin; TOP-53) in our search for a drug that has strong activity against lung cancer and lung metastatic cancer. TOP-53 exhibited twice the inhibitory activity of etoposide (VP-16) against topoisomerase II and induced DNA strand breaks but showed no inhibitory activity against tubulin polymerization. The in vitro cytotoxic activity of TOP-53 assessed as IC50 was 0.016-0.37 microg/ml and 0.26-8.9 microg/ml against marine tumor and human non-small cell lung cancer (NSCLC) cell lines, respectively. TOP-53 exerted significant efficacy equivalent to that of VP-16 on s.c.-implanted murine solid tumors (Colon 26, B16-BL6, and Lewis lung carcinoma) at doses 3-5 times lower than that of VP-16. In human tumor xenografts using NSCLC, TOP-53 was active for four of five tumors, whereas VP-16 was active for two of five tumors. Potent inhibitory activity of TOP-53 was also found against a lung tumor (Lewis lung carcinoma) and four lung metastatic tumors (NL-22 and NL-17 colon cancer, UV2237M fibrosarcoma, and K1735M2 melanoma). TOP-53 appeared to be more active against four of them than VP-16. Thus, TOP-53 is not only active against s.c.-implanted lung cancers but also strongly active against lung localized tumor and metastatic tumors in the lungs. The high selectivity of TOP-53 was attributed to its high distribution into the lung and its persistence. TOP-53 is expected to be highly effective against lung cancer including NSCLC and various lung metastatic tumors in the clinical field.
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PMID:Antitumor activity of a novel podophyllotoxin derivative (TOP-53) against lung cancer and lung metastatic cancer. 866 18

DNA topoisomerase II has been shown to be an important therapeutic target in cancer chemotherapy. Here, we describe studies on the antitumor activity of a novel topoisomerase II inhibitor, ER-37328 [12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1- jk]carbazole-4,6,10(5H,11H)-trione hydrochloride]. ER-37328 inhibited topoisomerase II activity at 10 times lower concentration than etoposide in relaxation assay and induced double-strand DNA cleavage within 1 h in murine leukemia P388 cells, in a bell-shaped manner with respect to drug concentration. The maximum amount of DNA cleavage was obtained at 2 microM. Like etoposide, ER-37328 (2 microM) induced topoisomerase II-DNA cross-linking in P388 cells. A spectroscopic study of ER-37328 mixed with DNA demonstrated that ER-37328 has apparent binding activity to DNA. ER-37328 showed potent growth-inhibitory activity against a panel of 21 human cancer cell lines [mean (50% growth-inhibitory concentration) GI50 = 59 nM]. COMPARE analysis according to the National Cancer Institute screening protocol showed that the pattern of the growth-inhibitory effect of ER-37328 was similar to that of etoposide, but different from that of doxorubicin. Studies on etoposide-, amsacrine [4'-(9-acridinylamino)methanesulfon-m-anisidide (m-AMSA)]-, and camptothecin-resistant P388 cell lines showed that: (a) etoposide- and m-AMSA-resistant P388 cell lines were partially resistant to ER-37328 compared with the parental cell line; and (b) a camptothecin-resistant cell line showed no cross-resistance to ER-37328. In addition, ER-37328 overcame P-glycoprotein-mediated resistance. In vivo, ER-37328 produced potent tumor regression of Colon 38 carcinoma inoculated s.c., and its activity was superior to that of etoposide or doxorubicin. These results indicate that ER-37328 inhibits topoisomerase II activity through the formation of topoisomerase II-DNA cleavable complex and has potent antitumor activity both in vitro and in vivo.
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PMID:Antitumor activity of ER-37328, a novel carbazole topoisomerase II inhibitor. 1246 11

12,13-Dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c] pyrimido[5,6,1-jk] carbazole-4,6,10(5H,11H)-trione hydrochloride (ER-37328) is a novel topoisomerase II poison with potent tumoricidal activity against solid tumor cells both in vitro and in vivo. Here, we describe studies on the effects of ER-37328 on the primary tumor, liver metastasis, and survival in a murine Colon 38 orthotopic transplantation model. When ER-37328 (10 mg/kg) was administered i.v. at 11 days or 20 days after transplantation, strong regression of the primary tumor was observed on both administration schedules. On the later schedule, ER-37328 completely blocked liver metastasis, whereas the mean number of metastases in the control group was 23.9. To examine the antitumor activity against Colon 38 at the liver in more detail, ER-37328 was administered to mice that had received an inoculation of Colon 38 tumor into the liver. ER-37328 showed strong tumor-regression activity against Colon 38 growing in the liver. In addition, administration of ER-37328 on a schedule of every 7 days four times caused a significant increase of 79% in life span in the orthotopic transplantation model, calculated by using mean survival times. Pharmacokinetic study revealed that ER-37328 was highly distributed to the tumor and organs. The ratios of the area under the concentration-time curves of ER-37328 in the tumor, lung, liver, and kidney versus plasma were 81, 77, 47, and 40, respectively. This high distribution to the tumor and liver may explain the potent antitumor activity of ER-37328 against Colon 38 tumor in the liver. In conclusion, the topoisomerase II poison ER-37328 is a promising candidate for clinical application against colon cancer.
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PMID:Effects of ER-37328 on primary tumor, liver metastasis, and life span in a murine colon 38 orthotopic transplantation model. 1253 73

We have discovered a novel topoisomerase II (topo II) poison, ER-37328 (12,13-dihydro-5-[2-(dimethylamino)ethyl]-4H-benzo[c]pyrimido[5,6,1-jk]carbazole-4,6,10(5H,11H)-trione hydrochloride), which shows potent tumor regression activity against Colon 38 cancer inoculated s.c. Here, we describe studies on the cell-killing activity against a panel of human cancer cell lines and the antitumor activity of ER-37328 against human tumor xenografts. In a cell-killing assay involving 1-h drug treatment, ER-37328 showed more potent cell-killing activity (50% lethal concentrations (LC50s) ranging from 2.9 to 20 microM) than etoposide (LC50s>60 microM) against a panel of human cancer cell lines. ER-37328 induced double-stranded DNA cleavage, an indicator of topo II-DNA cleavable complex formation, within 1 h in MX-1 cells, and the extent of cleavage showed a bell-shaped relationship to drug concentration, with the maximum at 2.5 microM. After removal of the drug (2.5 microM) at 1 h, incubation was continued in drug-free medium, and the amount of cleaved DNA decreased. However, at 10 microM, which is close to the LC50s against MX-1 cells, DNA cleavage was not detected immediately after 1-h treatment, but appeared and increased after drug removal. This result may explain the potent cell-killing activity of ER-37328 in the 1-h treatment. In vivo, ER-37328 showed potent tumor regression activity against MX-1 and NS-3 tumors. Moreover, ER-37328 had a different antitumor spectrum from irinotecan or cisplatin against human tumor xenografts. In conclusion, ER-37328 is a promising topo II poison with strong cell killing activity in vitro and tumor regression activity in vivo, and is a candidate for the clinical treatment of malignant solid tumors.
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PMID:A novel carbazole topoisomerase II poison, ER-37328: potent tumoricidal activity against human solid tumors in vitro and in vivo. 1270 85

The management of colorectal cancer relies heavily on the combination of the pyrimidine analog antimetabolite 5-fluorouracil with the platinum-based drug oxaliplatin or the topoisomerase inhibitor irinotecan. Optimization of dosing and scheduling of these agents to improve response and survival continues to evolve. Meanwhile, the rational targeting of molecular signaling pathways that are involved in the etiology of malignancies is currently one of the most promising strategies in novel anticancer drug development. New classes of drugs that target the epidermal growth factor receptor are among the most clinically advanced molecular-targeted therapies and have shown efficacy in colorectal cancer. The current status of epidermal growth factor receptor-targeted therapeutic agents is reviewed, with emphasis on their role in the management of colorectal cancer.
Dis Colon Rectum 2007 Aug
PMID:EGFR-targeted therapies in colorectal cancer. 1756 32

In the present investigation, the cytotoxic, hydroxyl radical scavenging and topoisomerase inhibition activities of Tabernaemontana divaricata (Apocynaceae) were evaluated. The extracts from leaves of the plant were prepared with different solvents viz. chloroform, methanol, ethyl acetate and hexane. In, in vitro cytotoxicity assay, with cell lines viz HCT-15 (Colon), HT-29 (Colon), 502713 (Colon), MCF-7 (Breast), PC- 3 (Prostrate), it was observed that the ethyl acetate extract was effective against only one colon cell line (502713) at the lowest dose i.e. 10 micro g/ml, whereas the chloroform extract was effective against all the three colon cancer cell lines, at 30 microg/ ml. In order to evaluate the mechanism of cytotoxicity of these extracts, they were assessed for their ability to scavenge hydroxyl radicals in plasmid nicking assay with pBR322. It was observed that all the extracts effectively inhibited the unwinding of supercoiled DNA except hexane extract, which showed the least effect. Since the expression of topo enzymes is linked with cell proliferation so the extracts were also checked for topo I and topo II inhibitory activities. It was noticed that ethyl acetate extract selectively showed inhibition of topo II in topoisomerase II relaxation assay.
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PMID:Studies on cytotoxic, hydroxyl radical scavenging and topoisomerase inhibitory activities of extracts of Tabernaemontana divaricata (L.) R.Br. ex Roem. and Schult. 1857 13