Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.3.1.21 (CPT)
 4,580 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

H 615, the first transplantable mouse liver carcinoma model established in China, was derived from a spontaneous hepatocellular carcinoma of an inbred 615 mouse and has been successfully propagated for 52 generations during the past 7 years and more. Its biologic and pathologic features are relatively stable. H 615 was a syngenic transplantable tumor model of 615-strain mice with a successful transplantation rate of 85.6% without spontaneous regression. The course of tumor growth after subcutaneous inoculation was divided into 4 stages: latent, slowly growing, rapidly growing and terminal stages. Cancer metastasis was rare. The tumor-bearing host would die of cachexia finally. The mean survival time was 62.2 +/- 11.0 days regardless of sex or age. Histologically and ultrastructurally, H 615 was a well-differentiated hepatocellular carcinoma, rather resembling human liver carcinoma. The short-term primary passage culture of H 615 showed that, in vitro, tumor tissue could easily grow into monolayer, the majority of which appeared as epithelioid cells in cytomorphology. Therapeutic tests of 15 anticancer drugs showed that H 615 was sensitive, in varying degrees, to 5 drugs, i. e. MMC, Thio-Tepa, 5FU, CPT and DACT. The inhibition rate of MMC and Thio-Tepa could be as high as 100%. These experimental results are similar to those of the human liver cancer chemotherapy. Hence, the authors believe that H 615 may be a useful model in experimental study of the liver cancer and screening of anticancer drugs.
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PMID:[Establishment and experimental study of a transplantable hepatocellular carcinoma model in 615-strain mice (H 615)]. 344 59

Among advanced ovarian cancer, OCCA has worse prognosis compared with serous cystadenocarcinoma because of its poor sensitivity to CDDP-based chemotherapy (CTX). Indeed, there has ever been no one patient with pure OCCA showing an appreciable response to CTX. OCCA has recently been increasing in prevalence and has occupied approximately 20-25% of all ovarian cancer. Thus, there is an urgent need to find effective regimens. Based on the results of chemosensitivity tests previously performed both in vitro and in vivo, we designed a combination of CPT (140 mg/m2, i.v.-infused over 4 hours on day 1, 15, and 29) and MMC (7 mg/m2, i.p. injection through a reservoir on day 1, 15, and 29). The course was repeated every 4 weeks. To date 10 pts were entered The median age was 53 (41-69). Among total 25 courses, grade 3 diarrhea was observed in 3 courses. Other toxic signs were acceptable. The responses by tumor size were 2 CR for disease < or = 2 cm in diameter, and 2 CR, 2 PR, 2 NC, and 2 PD for > 2 cm. Six responders showed a significantly longer survival compared with 4 non-responders (p < 0.0396 for Log-rank test). Thus, the present protocol is the first to demonstrate a significant activity for pure OCCA.
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PMID:[Successful treatment of clear cell adenocarcinoma of the ovary (OCCA) with a combination of CPT-11 and mitomycin C]. 867 17

Mitomycin C (MMC) is an anticancer drug that requires reductive activation to exert its toxicity. MMC is known to cross-link DNA that contributes significantly to the cytotoxicity and consequent cell death. Cytosolic NADPH:quinone oxidoreductase 1 (NQO1) and microsomal enzymes have been shown to mediate MMC-induced DNA cross-linking. However, NQO1 plays only a minor role, indicating presence of other cytosolic enzymes/proteins that contribute to this process. In this study, we have characterized a unique cytosolic activity in NQO1-null mice that catalyzed MMC-induced DNA cross-linking. This activity was cofactor independent and dicoumarol insensitive. The unique cytosolic activity was purified to homogeneity. The peptide sequencing of the purified protein identified the unique cytosolic activity as GRP58 (M(r) 58,000 glucose-regulatory protein), also known as GRp57/ER60/ERp61/HIP-70/Q2 and CPT. Immunodepletion of NQO1-null mice liver cytosol and partially purified fractions with anti-GRP58 antibody led to a complete loss of GRP58 protein and consequent significant reduction of MMC-induced DNA cross-linking. Mouse cDNA encoding GRP58 was isolated and sequenced. Chinese hamster ovary cells permanently overexpressing GRP58 showed increased MMC-induced DNA cross-linking and increased cytotoxicity on exposure to MMC. Bacterially expressed and purified GRP58 increased the MMC-induced DNA cross-linking when added to mouse cytosolic samples. A tissue array analysis indicated that GRP58 is ubiquitously expressed among mouse tissues, although at different levels. Expression analysis using matched human tumor/normal array revealed an up-regulation of GRP58 in breast, uterus, lung, and stomach tumors compared with normal tissues of similar origin.
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PMID:Role of GRP58 in mitomycin C-induced DNA cross-linking. 1452 30

Fanconi anemia (FA) patients exhibit bone marrow failure, developmental defects and cancer. The FA pathway maintains chromosomal stability in concert with replication fork maintenance and DNA double strand break (DSB) repair pathways including RAD51-mediated homologous recombination (HR). RAD51 is a recombinase that maintains replication forks and repairs DSBs, but also rearranges chromosomes. Two RecQ helicases, RECQL5 and Bloom syndrome mutated (BLM) suppress HR through nonredundant mechanisms. Here we test the impact deletion of RECQL5 and BLM has on mouse embryonic stem (ES) cells deleted for FANCB, a member of the FA core complex. We show that RECQL5, but not BLM, conferred resistance to mitomycin C (MMC, an interstrand crosslinker) and camptothecin (CPT, a type 1 topoisomerase inhibitor) in FANCB-defective cells. RECQL5 suppressed, while BLM caused, breaks and radials in FANCB-deleted cells exposed to CPT or MMC, respectively. RECQL5 protected the nascent replication strand from MRE11-mediated degradation and restarted stressed replication forks in a manner additive to FANCB. By contrast BLM restarted, but did not protect, replication forks in a manner epistatic to FANCB. RECQL5 also lowered RAD51 levels in FANCB-deleted cells at stressed replication sites implicating a rearrangement avoidance mechanism. Thus, RECQL5 and BLM impact FANCB-defective cells differently in response to replication stress with relevance to chemotherapeutic regimes.
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PMID:RECQL5 and BLM exhibit divergent functions in cells defective for the Fanconi anemia pathway. 2552 Jan 94