Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024623 (gastric cancer)
 36,219 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

CPT-11, a semisynthetic derivative of camptothecin, exhibited strong antitumor activity against lymphoma, lung cancer, colorectal cancer, gastric cancer, ovarian cancer, and cervical cancer. CPT-11 is a pro-drug that is converted to an active metabolite, SN-38, in vivo by enzymes such as carboxylesterase. We synthesized a water-soluble and non-pro-drug analog of camptothecin, DX-8951f. It showed both high in vitro potency against a series of 32 malignant cell lines and significant topoisomerase I inhibition. The anti-proliferative activity of DX-8951f, as indicated by the mean GI50 value, was about 6 and 28 times greater than that of SN-38 or SK&F 10486-A (Topotecan), respectively. These three derivatives of camptothecin showed similar patterns of differential response among 32 cell lines, that is, their spectra of in vitro cytotoxicity were almost the same. The antitumor activity of three doses of DX-8951f administered i.v. at 4-day intervals against human gastric adenocarcinoma SC-6 xenografts was greater than that of CPT-11 or SK&F 10486-A. Moreover, it overcame P-glycoprotein-mediated multi-drug resistance. These data suggest that DX-8951f has a high antitumor activity and is a potential therapeutic agent.
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PMID:A new water-soluble camptothecin derivative, DX-8951f, exhibits potent antitumor activity against human tumors in vitro and in vivo. 755 2

The cytotoxicity of SN-38, the major metabolite of CPT-11 (7-ethyl-10-[4-(1-piperidino)-1- piperidino]carbonyloxycamptothecin, was compared among gastrointestinal carcinomas of every organ, and between primary and metastatic lesions of every organ-originated gastrointestinal carcinoma, by an in vitro anticancer drug sensitivity test using fixed-contact-sensitive plates. The rates of cases having a high response (percent survival 75% or lower) to SN-38 but a low response (percent survival above 75%) to cisplatin, mitomycin C (MMC), adriamycin (ADM) and 5-fluorouracil (5-FU) were 14.6, 19.4, 15.6 and 27.0%, respectively. While, the rates of cases having a high response to cisplatin, MMC, ADM and 5-FU but a low response to SN-38 were 7.3, 2.8, 9.4 and 13.5%, respectively. Each of the former rates were higher than each of the latter rates. In particular, the former rate for MMC was significantly higher than the latter rate (p = 0.04). Two cases with colon cancer showed a high response only to SN-38. The percent survival of primary lesions in colon cancer was significantly lower than that in stomach cancer. The rates of hepatocellular carcinoma cases having a high response to SN-38 but a low response to cisplatin, MMC, ADM and 5-FU were 16.7, 16.7, 0 and 25%, respectively. Only one case had a high response to 5-FU but a low response to SN-38. The percent survival of metastatic lesions in pancreatic cancer was significantly lower than that of primary lesions. From this study, we recommend the further clinical trial of CPT-11 for colon and hepato-cellular cancers.
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PMID:Cytotoxicity of CPT-11 for gastrointestinal cancer cells cultured on fixed-contact-sensitive plates. 767 Jan 39

The purpose of this study was to screen 24 anti-cancer drugs, either in use or in clinical study, using four cell lines, all of which originated from poorly-differentiated gastric cancers. The MTT assay was used at 1, 6, 24 or 72 h exposure times as the chemosensitivity test. We also examined P-glycoprotein expression, mdr-1 gene amplification and the modifier effect of verapamil. All four cell lines generally showed the same chemosensitivity pattern, while GCIY cells showed mdr-1 gene amplification and P-glycoprotein expression, and KATOIII cells showed the multidrug resistant pattern without P-glycoprotein expression. Both cell lines acquired higher chemosensitivity after verapamil addition. All IC50 data (with or without verapamil) were multiplied by exposure time (delta IC50) and compared with the clinical 'area under the concentration curve (AUC)'. SN-38 with/without verapamil, cisplatin with verapamil and pirarubicin with/without verapamil seemed to be the best candidates for poorly-differentiated gastric cancer chemotherapy. Plant alkaloids could also be candidates. With further experiments, we may be able to deduce commonly effective chemotherapy for poorly-differentiated gastric cancer from these drugs.
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PMID:Selection of three out of 24 anti-cancer agents in poorly-differentiated gastric cancer cell lines, evaluated by the AUC/delta IC50 ratio. 779 77

Lung resistance-related protein (LRP) is the human major vault transporter protein and is suggested to confer anticancer drug resistance. We quantitated the level of LRP mRNA expression in 10 gastric and 14 lung cancer cell lines by RT-PCR, and examined the relationship between its level in these cells and their sensitivities to anticancer drugs. HT1080 fibrosarcoma cells were used as positive controls for LRP. LRP mRNA was expressed in all gastric and lung cancer lines, and its level in each cell type was less than two-fold that of HT1080 cells, except for two lung cancer lines. The correlation between the level of LRP mRNA expression and cisplatin sensitivity was significant in lung cancer lines (r = 0.762, P = 0.028), and borderline in gastric cancer lines (r = 0.631, P = 0.129). There was no correlation between the level of LRP mRNA expression and etoposide, doxorubicin, vincristine, or SN-38. Our results suggest that LRP is commonly expressed in gastric and lung cancers, and may confer their resistance to cisplatin.
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PMID:Lung resistance-related protein gene expression and drug sensitivity in human gastric and lung cancer cells. 971 13

CPT-11 is a comptothecin analogue which has shown a broad spectrum of strong antitumor effect against various cancers, including gastroenterological malignancies. In the present study, the antitumor effect of CPT-11 was determined by MTT assay for freshly isolated human gastric and colorectal cancer cells, especially highly purified tumor cells. Twenty-three patients with gastric cancer, and 32 patients with colorectal cancer were enrolled in this study. Three gastric and 3 colonic cancer cell lines were used to study the antitumor effect of CPT-11, and freshly isolated cancer cells from 3 patients with gastric cancer were investigated. The in vitro antitumor effect was tested by MTT assay, and showed % inhibition rate. CPT-11 and SN-38 showed the antitumor effect as a dose dependent matter for human gastric and colorectal tumor cells in vitro. From the results of chemosensitivity for freshly isolated gastric and colorectal tumor cells, antitumor effect of SN-38 was as strong as other conventional anticancer agents. It was demonstrated that the MTT assay was appropriate for the analysis of the antitumor effects of CPT-11 and SN-38, and that CPT-11 may be a worthwhile choice as an anticancer agent against gastric and colorectal cancer.
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PMID:In vitro antitumor effect of topoisomerase-I inhibitor, CPT-11, on freshly isolated human gastric and colorectal cancer. 1069 76

The metabolism of CPT-11 in malignant ascites of gastric cancer patients with peritoneal seedings was studied in advance of the intraperitoneal chemotherapy of CPT-11 in humans. Malignant ascites and blood were drawn from gastric cancer patients. CPT-11 solution (20 mg/ml; 0.2 ml) was added into 3.8 ml ascites or plasma under 37 degrees C and CPT-11, SN-38 and SN-38GLU concentrations were measured with HPLC at times of 5, 30 and 60 minutes after addition of CPT-11. The change from CPT-11 to SN-38 was minimal not only in plasma, but also in malignant ascites. SN-38 GLU concentration was below the limit of measurement. This study showed that in malignant ascites, the enzymes such as carboxyesterase that convert CPT-11 to SN-38 were not present or minimal.
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PMID:[Experimental study on CPT-11 intraperitoneal chemotherapy--metabolism of CPT-11 in malignant ascites]. 1108 30

Activation of proteases can play an important role in apoptotic cell death induced by anticancer drugs. To assess involvement of activation of cysteine and serine proteases in anticancer drug-induced apoptosis, we tested effect of inhibitors of cysteine and serine proteases on sensitivity to anticancer drugs in MKN45 gastric cancer cells. Cytotoxic effect by adriamycin (ADM), SN-38 (active form of irrinotecan) and cisplatin (CDDP) was significantly prevented by cotreatment with Z-Val-Ala-Asp-fluoromethylketone (Z-VAD-fmk) (p<0.01), a pancaspase inhibitor compared with drug alone using MTT assay. In contrast, cotreatment with N-acetyl-Tyr-Val-Ala-Asp aldehyde (AC-YVAD-CHO), a caspase 1 inhibitor did not prevent any cytotoxic effect of these drugs. Cotreatment of N-acetyl-Asp-Glu-Val-Asp aldehyde (AC-DEVD-CHO), a caspase 3 inhibitor prevented cytotoxic effect of VP-16 and SN-38 (p<0.01). Prevention of these cytotoxic effects by caspase inhibitors was not dose-dependent. Cotreatment of N-tosyl-L-lysyl chloromethylketone (TLCK), a serine protease inhibitor significantly prevented cytotoxic effect of ADM, SN-38, 5-fluorouracil (5-FU) and CDDP in a slight dose-dependent manner (p<0.01) except for etoposide (VP-16) and docetaxel (TXT), while an other serine protease inhibitor, N-tosyl-L-phenylalanyl chloromethylketone (TPCK) did not prevent any anticancer drug-induced cytotoxic effect. These effects were associated with prevention of internucleosomal DNA ladder formation in apoptosis. Further, protease inhibitors did not block induction of cytochrome c, that can explain the partial effect of prevention by anticancer-induced cell death. These results suggest that anticancer drug-induced cytotoxic effect is mediated by activation of serine protease (caspase-independent) as well as caspase-dependent pathway leading to apoptotic cell death, and that protease-independent pathway may also be involved in apoptotic pathways. The involvement of protease in signal transduction pathways may differ in cytotoxic action of drugs in gastric cancer cells.
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PMID:Effect of inhibitors of cysteine and serine proteases in anticancer drug-induced apoptosis in gastric cancer cells. 1135 Dec 55

We studied the pharmacokinetics of the intraperitoneal administration of CPT-11 for four patients with peritoneal metastasis (2 gastric cancer cases, 2 colon cancer cases). CPT-11 was administrated in a dose of 40-60 mg and the intraperitoneal and serum levels of CPT-11, SN-38 and SN-38 glucuronized (SN-38 Glu) were measured periodically. Intraperitoneal therapy with CPT-11 was effective for the control of malignant ascites. No serious side effects were observed. The levels of CPT-11, SN-38 were no different 30 min afterwards the administration of CPT-11 either intraperitoneally or intravenously. The high concentration of CPT-11 was achieved with intraperitoneal therapy and a small fraction of CPT-11 changed into SN-38 in the abdominal cavity.
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PMID:[Pharmacokinetic study of the intraperitoneal administration of CPT-11 for patients with peritoneal seedings of gastric and colonic cancers]. 1170 65

BACKGROUND: Because chemosensitivity tests usually require a large amount of tissue, they are not used routinely in patients with unresectable gastric cancer. The aim of this study was to investigate whether apoptosis can be used as a sensitivity assay for chemosensitivity in small gastric cancer specimens.METHODS: Apoptosis, detected by terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick labeling (TUNEL), was investigated in small specimens of the MKN-1, MKN-45, and TMK-1 human gastric cancer cell lines as a marker of chemosensitivity following exposure to antineoplastic agents.RESULTS: Doxorubicin (DXR), SN-38 (active metabolite of irinotecan), and paclitaxel (Taxol) induced DNA fragmentation in MKN-45 and TMK-1 cells, but not in MKN-1. In contrast, neither 5-fluorouracil (5-FU) nor cisplatin (CDDP) induced DNA fragmentation in any of the three cell lines. Small pieces cut from tumors implanted in nude mice were exposed to the antineoplastic agents in culture medium for 24 h, and the percentage of TUNEL-positive cancer cells (TUNEL positivity) was examined. TUNEL positivity in all three cancers increased after exposure to DXR, SN-38, and Taxol, but not after exposure to CDDP or 5-FU. MKN-45 showed the highest TUNEL positivity with SN-38 and Taxol, and TMK-1 TUNEL positivity was highest with DXR. MKN-45 and TMK-1 were the most sensitive to these three antineoplastic agents in vitro, while MKN-1, with the lowest TUNEL positivity, was the least sensitive to these three antineoplastic agents. TUNEL positivity after exposure to Taxol correlated with the antitumor effects of this compound in an animal model.CONCLUSION: These results suggest that, in small gastric cancer specimens where apoptosis is implicated, TUNEL positivity may be applicable to a chemosensitivity test.
Gastric Cancer 2000 Aug 04
PMID:A model chemosensitivity test examining apoptosis in small specimens of gastric cancer. 1198 8

The anti-metastatic efficacy of MMI-166, which is a selective matrix metalloproteinase (MMP) inhibitor, in combination with CPT-11 was examined using two metastasis models of human gastrointestinal cancer cells. In the liver metastasis model, C-IH human colon cancer cells were injected into the spleen of athymic BALB/c nude mice. Daily oral (p.o.) dosing of MMI-166 at 200 mg/kg starting 1 day after tumor inoculation led to a significantly prolonged survival effect by inhibiting liver metastasis of C-1H tumor cells. CPT-11 (5 or 20 mg/kg) was administered intraperitoneally (i.p.) three times on day 3, day 7 and day 11 and also improved the survival of tumor-inoculated mice compared with the vehicle control. When MMI-166 was combined with CPT-11, the anti-metastatic efficacy was significantly augmented. Moreover, long tumor-free survival was noted in two of eight mice that were given the combination therapy but not either MMI-166 or CPT-11 monotherapy. In the peritoneal dissemination model, TMK-1 human gastric cancer cells were injected i.p. into nude mice. While both MMI-166, administered daily p.o. from day 1 at 200 mg/kg, and CPT-11, administered intravenously (i.v.) three times, inhibited the tumor dissemination and growth, the combination therapy of MMI-166 plus CPT-11 showed a greater inhibitory effect than each monotherapy. A hematotoxicity study demonstrated that CPT-11 alone significantly decreased the number of white blood cells (WBC) and bone marrow cells (BMC) in the mice during treatment, while the daily administration of MMI-166 alone had no such effect. More importantly, the combination therapy of MMI-166 with CPT-11 did not augment the hematotoxicity caused by CPT-11. An in vitro cytotoxicity study showed that MMI-166 itself neither has direct cytotoxicity in C-1H and TMK-1 tumor cells, nor does it augment the cytotoxicity of SN-38, an active form of CPT-11. The findings indicate that the augmented anti-metastatic efficacy in combination treatment was not simply due to the augmentation of direct cytotoxic activity, but was rather an additive or synergistic effect of anti-metastatic activities with different mechanisms. In conclusion, we demonstrated that the anti-metastatic efficacy against C-1H colon cancer and TMK-1 gastric cancer were augmented by the combination therapy of MMI-166, an orally active MMP inhibitor, with CPT-11. However, the hematotoxicity caused by CPT-11 was not augmented in the combination with MMI-166. Thus, the combination therapy of MMI-166 and CPT-11 exhibited potent anti-metastatic efficacy without increased hematotoxicity. These results point to the clinical advantage of using MMI-166 in combination with CPT-11.
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PMID:Augmented anti-metastatic efficacy of a selective matrix metalloproteinase inhibitor, MMI-166, in combination with CPT-11. 1240 89


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