Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Oxaliplatin is a new platinum analog of the DACH family. Recent preclinical data have confirmed its non overlapping spectrum of activity with cisplatin, including acquired and intrinsic platinum resistant cell lines (as KB-CP, A 2780, HT29, CaCo2 colon cancer). When combined with other cytotoxic agents (5FU, SN38, CDDP, carboplatin), oxaliplatin has additive and/or synergistic antitumoral effects on various in vitro and in vivo models (colon, breast, ovarian and epidermoid tumors). Phase II trials have confirmed a sensorial peripherical neuropathy as its limiting toxicity while neither ototoxicity nor renal toxicities and only limited myelotoxicity were noted. Available phase II studies have established its antitumoral activity as single agent in 5FU refractory colon carcinoma while preliminary results suggest efficacy in cisplatin resistant ovarian cancer, in non small cell lung cancer, non Hodgkin lymphoma. Antitumoral activity has been observed during phases 1 in melanoma, glioma, breast and oesophageal cancers. A high response rate (28-65%) with the triple association (FU/folinic acid/oxaliplatin) has been reported in advanced colon cancer treated in first and second line settings. The results of two randomized phase III studies (FU/folinic acid +/- oxaliplatin) are expected. The oxaliplatin/cisplatin combination as salvage regimen had produced significant antitumoral activity (response rate: 45%) in resistant/refractory ovarian cancer. Finally, recent experimental and clinical data have outlined the potential interest in the development of this new original platinum compound. New single agent phases II are expected in other tumor types as well as new oxaliplatin combinations are ongoing (phase I trials of oxaliplatin/CPT-11 and of oxaliplatin/carboplatin, phase II study of oxaliplatin-vinorelbine in lung cancer.
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PMID:[Oxaliplatin: the first DACH platinum in clinical practice]. 929 71

Camptothecin (CPT) is a specific topoisomerase I (top1) poison which traps top1 cleavable complexes; e.g. top1-linked DNA single-strand breaks with 5'-hydroxyl and 3'-top1 linked termini. CPT is also a potent anticancer agent and several of its derivatives have recently shown activity in the chemotherapy of solid tumors. Our aim was to apply the ligation-mediated polymerase chain reaction (LM-PCR) method to DNA extracted from CPT-treated cells in order to: (i) evaluate LM-PCR as a sensitive technique to detect in vivo CPT-induced cleavable complexes; (ii) investigate the frequency and distribution of CPT-induced DNA damage in vivo ; and (iii) compare the distribution and intensity of cleavage sites in vivo and in vitro. This report describes a protocol allowing the sequencing of top1-mediated DNA strand breaks induced by CPT in the coding strand of the 18S rRNA gene of human colon carcinoma cells. CPT or its clinical derivatives, topotecan, CPT-11, SN-38, and 9-aminocamptothecin differed in their potency and exhibited differences in their DNA cleavage pattern, which is consistent with our previous in vitro studies [Tanizawa et al . (1995) Biochemistry , 43, 7200-7206]. CPT-induced DNA cleavages induced in the presence of purified top1 were induced at the same sites in the human 18S rDNA. However, the relative intensity of the cleavages were different in vivo and in vitro. Because mammalian cells contain approximately 300 copies of the rDNA gene per genome, rDNA could be used to monitor CPT-induced DNA cleavage in different cell lines and possibly in tumor samples.
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PMID:In vivo sequencing of camptothecin-induced topoisomerase I cleavage sites in human colon carcinoma cells. 932 66

DX-8951 is a novel water-soluble derivative of camptothecin. We evaluated the effects of DX-8951 on the growth of several pancreatic tumor cell lines in vitro and in vivo. In vitro cytotoxic activity of DX-8951 against SUIT-2 and KP-1N cells, as indicated by IC50 value, was several times more potent than that of SN-38, an active metabolite of CPT-11, and dozens of times more potent than that of SK&F104864 (topotecan). DX-8951 also showed the greatest cytotoxicity against CPT-11-resistant variants, SUIT-2/CPT-11 and KP-1N/CPT-11 cells, and the cross-resistance of these cells to DX-8951 was lower than that to SN-38 and SK&F104864. Topoisomerase I inhibitory activity of DX-8951 was about three-fold stronger than that of SN-38, as measured in crude nuclear extract obtained from SUIT-2 cells. DX-8951 induced DNA fragmentation, a specific feature of apoptosis, in SUIT-2 cells more effectively than SN-38. DX-8951 exhibited potent antitumor effects against SUIT-2 in a solid tumor model and in a liver metastasis model, in which tumor cells were xenografted subcutaneously and intrasplenically, respectively, into nude mice. The in vivo effects were closely similar to or somewhat superior to those of CPT-11. DX-8951 also showed significant antitumor effects against SUIT-2/CPT-11 solid tumors, against which CPT-11 had no effect. These results suggest that, on the basis of its strong antitumor activity and effectiveness against CPT-11-resistant tumors, DX-8951 may be a useful therapeutic agent in the treatment of human cancer. The potent cytotoxicity of DX-8951 may result from strong inhibition of topoisomerase I, which may then trigger apoptotic cell death.
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PMID:Antitumor effect of DX-8951, a novel camptothecin analog, on human pancreatic tumor cells and their CPT-11-resistant variants cultured in vitro and xenografted into nude mice. 933 Jun 8

The anti-tumor activity of irinotecan (CPT-11), a DNA-topoisomerase 1 inhibitor, was evaluated in 5 advanced stage subcutaneous medulloblastoma xenografts in nude mice, using different schedules of administration. With a 5-day schedule, the highest i.v. dose tested (40 mg kg-1 day-1) induced complete regressions in all xenografts but 1, and delays in tumor growth always exceeded 30 days. Two xenografts, IGRM11 and IGRM33, were highly sensitive, and animals survived tumor-free beyond 120 days after treatment. CPT-11 clearly retained its anti-tumor activity at a lower dosage (27 mg kg-1 day-1). CPT-11 was significantly more active than cyclophosphamide, thiotepa and etoposide against the 3 xenografts evaluated. To study the schedule dependency of its anti-tumor activity, CPT-11 was given i.v. at the same total doses over the same period (33 days) using either a protracted or a sequential schedule in IGRM34-bearing mice. With a dose of 10 mg kg-1 day-1 given on days 0-4, days 7-11, days 21-25 and days 28-32 (total dose, 200 mg kg-1), 3 of 6 animals were tumor free on day 378. The same total dose given with a sequential schedule, i.e., 20 mg kg-1 day-1 on days 0-4 and days 28-32, failed to induce complete regression. The plasma pharmacokinetics of CPT-11 and SN-38 were studied in IGRM34-bearing animals after a single i.v. dose of 10 and 40 mg kg-1. The plasma clearance rate of CPT-11 was dose dependent. The ratio between the SN-38 and CPT-11 area under the curve in plasma was 0.4-0.65, i.e., significantly higher than that observed in humans at the maximum tolerated dose (0.01-0.05). Conversely, this ratio was 10-fold lower in tumor than in plasma. Clinical development of irinotecan is warranted in pediatric malignancies.
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PMID:Potent therapeutic activity of irinotecan (CPT-11) and its schedule dependency in medulloblastoma xenografts in nude mice. 933 24

Prevention of cigarette smoking and early lung cancer detection remain important in our approach to the control of non-small cell lung cancer (NSCLC). In recent years, chemotherapy has emerged as a viable option in the treatment of NSCLC. The most impressive and widely confirmed evidence for this is the fact that chemotherapy can eradicate NSCLC micrometastases. Indeed, in some studies employing neoadjuvant chemotherapy followed by local surgery, pathology-confirmed complete remission rates as high as 20% have been reported. New agents showing preliminary activity in NSCLC include paclitaxel, vinorelbine, gemcitabine, and irinotecan (CPT-11). Certainly, however, there remains a need for novel, effective single-agent and combination chemotherapies. The seed/soil tumor concept, in which the seed consists of the tumor cells per se and the soil is the stroma containing the seeds, has proven helpful in devising new treatment strategies. Such strategies may include the use of antisoil agents, including antiangiogenesis, anti-invasion, and antimetastasis agents, both separately and particularly in conjunction with established antitumor agents. New therapeutic targets and methods of antitumor agent development based on modern molecular biology and pharmacology will provide a greater opportunity to improve the treatment of NSCLC.
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PMID:Non-small cell lung cancer: novel treatment strategies. 933 1

The purpose of this study was to describe a new anti-cancer drug regimen for uterine cervical cancer. The cytotoxicities of some anti-cancer drugs regimens against the human uterine cervical cancer xenografted into nude mice have been studied. The activities of CDDP, CPT-11, TXL, CDDP + BLM, CDDP + MMC, CPT-11 + BLM, CPT-11 + CDDP, CDDP + 5-FU, CPT-11 + MMC, CPT-11 + TXL and CDDP + TXL for squamous cell carcinoma (TCR, TCK, TCG), and CDDP, MMC, TXL, CDDP + TXL, CDDP + MMC and MMC + TXL for adenocarcinoma (TCO, TCM, TCY), were evaluated comparing with a control group using saline. Five mice were used for each groups. When the xenografted tumor reached 6 mm in diameter, 1/5 LD50 of these drugs were administered into the peritoneal cavity of the mice once a week for three weeks. The effective regimens were CDDP + MMC, CDDP + BLM, CDDP + CPT-11 and CPT-11 + MMC for squamous cell carcinoma of the uterine cervix. CDDP + MMC, CDDP + TXL, MMC + TXL and CDDP were effective for endocervical adenocarcinoma. It was suggested that these new drug regimens should be used in clinical studies.
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PMID:[Evaluation of a new anti-cancer drug regimen against uterine cervical cancer in nude mice]. 935 Feb 46

CPT-11, a semi-synthetic derivative of camptothecin, was investigated for its activity in panels of 15 human ovarian-cancer lines and 10 human soft-tissue sarcoma lines grown s.c. in nude mice. Various factors were analyzed that may be of influence on the extent of tumor-growth inhibition induced by CPT-11. At equitoxic doses, CPT-11 was more effective in the daily x5 schedule than the weekly x2 schedule, although a 2-fold higher dose was administered in the weekly x2 schedule. Since i.p. and i.v. injections were similarly effective, the selected treatment schedule was 20 mg/kg i.p. daily x5, starting when tumors measured approximately 150 mm3. Growth inhibition of > or = 75% was obtained in 8/15 human ovarian-cancer lines and in 6/10 human soft-tissue sarcoma lines. A weak correlation was found between topoisomerase-I mRNA in xenograft tissues and sensitivity to CPT-11. Relative topoisomerase-I expression was highest in MRI-H-207 and WLS-160 xenografts, in which CPT-11 was able to induce cures of all tumors. The high efficacy in the 2 panels of human tumor lines suggests over-prediction of its potential clinical activity in these tumor types. The difference in efficacy of CPT-11 between species may be related to the metabolism of the drug, since CPT-11 is converted more efficiently into SN-38 in mice. In addition, mice may be less sensitive to SN-38-induced side-effects. On the basis of the preclinical data, frequent administration of lower doses of CPT-11 should be considered in order to increase response rates in the clinic.
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PMID:Anti-tumor activity of CPT-11 in experimental human ovarian cancer and human soft-tissue sarcoma. 939 72

A novel quinoline derivative, TAS-103 (6-[[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin -7-one dihydrochloride), was developed as an anticancer agent targeting topoisomerases (topo) I and II, with marked efficacy in solid tumors. TAS-103 inhibited topo I and II (IC50: 2 microM, 6.5 microM) at a concentration similar to or lower than those of previous agents, and had a strong cytotoxic effect on P388 and KB cells (IC50: 0.0011 microM, 0.0096 microM). TAS-103 stabilized topo I and II-DNA cleavable complexes in KB cells, generating a similar amount of topo II-DNA complex to that induced by etoposide (VP-16) but a smaller amount of topo I-DNA complex than that produced by camptothecin (CPT). In the in vivo study, intermittent i.v. administration was markedly effective against s.c.-implanted murine tumors. Furthermore, TAS-103 had marked efficacy against various lung metastatic tumors, and a broad antitumor spectrum in human tumor xenografts (derived from lung, colon, stomach, breast, and pancreatic cancer). The efficacy of TAS-103 was generally greater than that of irinotecan (CPT-11), VP-16, or cis-diamminedichloroplatinum (CDDP).
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PMID:Antitumor activity of a novel quinoline derivative, TAS-103, with inhibitory effects on topoisomerases I and II. 941 62

Evolving trends in the management of rectal cancer have focused on organ preservation, improved quality of life, and survival of patients. A significant shift is underway in our thinking about what constitutes the true rectum and defining the "proximal" and "distal" segments of the rectum. Tumor mobility remains a dominant prognostic factor in patient selection and choice of surgery. A clinical staging with tumor location in the rectum provides a logical algorithm for treatment decision making with either chemoradiation therapy or surgery as initial treatment of choice. Current rectal cancer management has largely focused on postoperative adjuvant radiation strategies with improvement reported for T3 and N+ cases. Recent data from Europe suggests that preoperative radiation has a significant advantage over surgery alone or postoperative treatment. This appears to be borne out by institutional studies of high-dose preoperative radiation (>45 Gy) in the United States. Aggressive preoperative combined chemoradiation has also led to significant downstaging of cancer with pathological complete response rates of 20% to 30%. This offers new options for surgical management of residual disease with endocavitary radiation or local excision. The development of new agents Gemcitabine, paclitaxel, and CPT-11 may also prove beneficial. New treatment strategies need to be coordinated with evolving knowledge of the biological behavior of the tumor based on its genetic fingerprints. c-Ki-ras and C-myc mutations have been implicated in tumor initiation and progression. A number of other tumor suppressor genes, APC gene, p53, and DCC have also been implicated in colorectal tumor carcigenesis. The modification of biological behavior by mutations in these genes is currently under study. This may guide new treatment strategies significantly reducing the death rates from rectal cancer and improving functional results of treatment.
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PMID:Critical issues in the evolving management of rectal cancer. 942 68

A cell line derived from human endometrial clear cell adenocarcinoma was newly established and named TEN. The tumor cells were obtained from uterine body of a 74-year-old who had been undergone an abdominal simple hysterectomy. The histologic features of the tumor cells showed abundant clear cytoplasm with diastase digested glycogen granule growing in solid nest and tubular pattern. The TEN cells were continuously propagated in vitro during the past 45 months and they were at 75th passage. They grew in a monolayered sheet with a doubling time of about 53 hours. The TEN cells resembled the structure of the original tumor and had abundant glycogen granules, lipid droplets in the cytoplasm. The histopathology of the transplanted tumor in SCID mice resembled that of the original tumors. The TEN cells secreted a high content of CA125. Immunohistochemically, the TEN cells had c-erbB-2 and Cathepsin D immunoreactivity in some parts of the cell population. But they did not have estrogen, progesterone and EGF receptor. Sensitivities of the TEN cells to a variety of anti-cancer drugs were examined. In in-vitro tests, MTT assays employed. The results suggested that the TEN cells were not sensitive to any of 13 agents. On the other hand, in-vivo sensitivity test of transplanted tumor in SCID mice, the tumors were sensitive to CPT-11 and paclitaxel. We conclude that the TEN cell line will be effective material for chemosensitivities against the endometrial clear cell adenocarcinoma.
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PMID:Characterization of a newly established human tumor cell line (TEN) from a patient with clear cell carcinoma of the uterine body and its sensitivity to anti-cancer agents. 943 40


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