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)

Water-soluble 20(S)-glycinate esters of two highly potent 10,11-methylenedioxy analogues of camptothecin (CPT) have been synthesized and evaluated for their ability to eradicate human breast cancer tumor xenografts. The glycinate ester moiety increases the water solubility of the 10,11-methylenedioxy analogues 4-16-fold. However, in contrast to CPT-11, a water-soluble CPT analogue that was recently approved for second line treatment of colorectal cancer, the 20(S)-glycinate esters do not require carboxylesterase for conversion to their active forms. The glycinate esters are hydrolyzed to their parent, free 20(S)-hydroxyl active analogues in phosphate buffer (pH 7.5) and in mouse and human plasma. The glycinate esters are also 20-40-fold less potent than CPT-11 in inhibiting human acetylcholinesterase. In vivo, we examined 20(S)-glycinate-10,11-methylenedioxycamptothecin, 20(S)-glycinate-7-chloromethyl-10,11-methylenedioxycamptothecin, and CPT-11. We found that the two 10,11-methylenedioxy analogues had antitumor activity against breast cancer xenografts that was comparable to that of CPT-11. Our results indicate that water-soluble 20(S)-glycinate esters of highly potent CPT analogues provide compounds that maintain biological activity, do not require interactions with carboxylesterases, and do not inhibit human acetylcholinesterase.
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PMID:Water soluble 20(S)-glycinate esters of 10,11-methylenedioxycamptothecins are highly active against human breast cancer xenografts. 1041 5

Irinotecan (CPT-11) is a derivative of the chemotherapeutic agent camptothecin. CPT-11 inhibits the nuclear enzyme topoisomerase I. It has demonstrated a broad spectrum of antitumor activity in preclinical tumor model systems. Significant advances have been made toward the understanding of the pharmacokinetics and schedule dependency of this agent. CPT-11 has demonstrated significant clinical activity in the treatment of patients with gastrointestinal, pulmonary, gynecologic, and lymphoid malignancies. Further study of this agent to determine its role in combination chemotherapeutic regimens is currently underway.
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PMID:A review of the clinical experience with irinotecan (CPT-11). 1042 12

This study was designed to determine if histopathologic evaluation of patients with resectable colorectal cancer following preoperative chemotherapy with uracil and tegafur with a molar ratio of 4:1 (UFT) could predict chemosensitivity to postoperative fluoropyrimidines to prevent recurrence of disease. In this prospective randomized study involving 152 colorectal cancer patients, UFT 600 mg/day was administered for 10 days prior to surgery. Histopathology of the resected tumor was assessed, including the amount of necrosis or disappearance of tumor, and patients were thereafter stratified into two groups according to tumor response to preoperative therapy--grade > or = 2 (sensitive) vs those with grade < or = 1B (not sensitive). The patients were then randomly assigned to postoperative adjuvant UFT (400 mg/day for 12 months) or no treatment. At the time of this evaluation, the mean total preoperative UFT dose per patient was 7.76 g +/- 3.27 g. Thirteen patients were considered ineligible; therefore, 139 patients were included in the analysis. Stratification resulted in 22 (15.8%) cases in the sensitive group, of which 13 received adjuvant chemotherapy and nine were assigned to no treatment; 117 (84.2%) patients were considered nonsensitive, 60 of whom received adjuvant chemotherapy, and 57 of whom received no adjuvant therapy. Among nonsensitive patients, 3-year survival rates were 87.6% with adjuvant chemotherapy and 84.9% with no therapy, indicating no significant difference between groups. Among responders, however, there was a significant difference in 3-year survival rates: 100% for the adjuvant group and 62.5% for the no-treatment group (P = .0351). These findings suggest that histopathologic assessment following preoperative UFT chemotherapy provides information to predict fluoropyrimidine sensitivity. We believe grade 1B patients (19.8%) may respond to modulated fluorouracil. We also recommend the use of other drugs, such as irinotecan (CPT-11 [Camptosar]) and oxaliplatin, for patients with tumor responses of grades 0 and 1A.
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PMID:Using preoperative UFT to predict sensitivity to fluoropyrimidines in colorectal cancer. 1044 63

Stimulated by surprising results in the first 7 patients treated with intraarterial/systemic chemotherapy with a combination of Mitomycin-C + Gemcitabine we now report on the data of 28 pancreatic cancer patients in comparison to 15 patients treated with gemcitabine alone(1000 mg/m2). Tumor response was evaluated on the basis of imaging methods, tumor markers and life quality parameters like body weight, pains and Karnofsky index etc. Tumor markers were monthly determined, imaging methods every 1-3 months. The locoregional/systemic approach included 3 week cycles with i.a. application of mitomycin-C + gemcitabine on day 1 and i.v. application of gemcitabine on days 8 and 15. The alltogether 125 cycles (mean 4 cycles per patient) resulted in 43% PR (n = 12), 1 CR (3%), 255 MR, 11% SD and 18% PD in the imaging methods and 20% CR, 60% PR, 4% MR and 12% SD in the course of the relevant tumor markers. Progression free survival amounted to a median of 7.5 (6) months defined by imaging methods (tumor markers). Second line treatments following new progress after effective locoregional approach with gemcitabine or a combination of gemcitabine + oxaliplatin did not result in a new tumor regression. However, third line therapy trials in 3 patients with high dose 5-FU or CPT 11 induced new antitumoral efficacy (survival of these tumors > 15, > 17 and > 28 months, n = 2 M1, n = 1 T3M0). About 75% of patients reported on a relevant benefit of life quality parameters. Side effects are on principle comparable to those of gemcitabine monotherapy, except for a tendency to a higher rate of pulmonary complications and 1 HUS observed. Even if not compared in a randomized study locoregional/systemic combined treatment modality seems to result in a higher rate of abjective tumor response defined by imaging methods as well as tumormarkers. Comparing tumor marker and imaging response to therapy CA 19-9 often showed a more rapid and subtle answer to therapy and an earlier new increase suggesting tumor markers as an essential part in the follow-up of these patients in order to optimize the patient's palliative treatment. Our results should stimulate the clinicians to rediscuss the chemosensitivity of exocrine pancreatic cancer and to perform prospective randomized studies focusing on combined gemcitabine approaches.
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PMID:Locoregional/systemic chemotherapy of locally advanced/metastasized pancreatic cancer with a combination of mitomycin-C and gemcitabine and simultaneous follow-up by imaging methods and tumor markers. 1047 Jan 75

Although topoisomerase inhibitors, such as camptothecin and topotecan, have been widely used in the treatment of nonglial tumors, their application for gliomas has been limited by poor efficacy relative to toxicity that may in part reflect limited bioavailability and blood stability of these agents. However, the potential promise of this class of agents has fostered efforts to develop new, more potent, and less toxic inhibitors that may be clinically relevant. Using a cascade radical annulation route to the camptothecin family, we developed a series of novel camptothecin analogues, 7-silylcamptothecins ("silatecans"), that exhibited potent inhibition of topoisomerase I, dramatically improved blood stability, and sufficient lipophilicity to favor blood-brain barrier transit. We explored the efficacy of a series of these agents against a panel of five high-grade glioma cell lines to identify a promising compound for further preclinical testing. One of the most active agents in our systems (DB67) inhibited tumor growth in vitro with an ED50 ranging between 2 and 40 ng/ml, at least 10-fold more potent than the effects observed with topotecan, and at least comparable with those of SN-38, the active metabolite of CPT-11. Because DB67 also exhibited the highest human blood stability of any of the agents examined, this agent was then selected for in vivo studies. A dose-escalation study of this agent in a nude mouse U87 glioma model system demonstrated a concentration-dependent effect, with tumor growth inhibition at day 28 postimplantation (the day control animals began to require sacrifice because of large tumor size) of 61 +/- 7% and 73 +/- 3% after administration of DB67 doses of 3 and 10 mg/kg/day, respectively, for 5 days beginning on postimplantation day 7. Animals that continued treatment with 10 mg/kg/day in three additional 21-day cycles all remained progression free after >90 days of follow-up but later developed enlarging tumors after treatment was stopped. However, a slightly higher dose (30 mg/kg/day) induced complete tumor regression after only two cycles in all study animals and was effective even if treatment was delayed until large, bulky tumors had developed. Application of the 30 mg/kg/day dose to treat established intracranial glioma xenografts led to long-term (>90 day) survival in six of six animals, whereas all controls died of progressive disease (P < 0.00001). No apparent toxicity was encountered in any of the treated animals. In summary, the present studies indicate that silatecans may hold significant promise for the treatment of high-grade gliomas and provide a rationale for proceeding with further preclinical evaluation of their efficacy and safety versus commercially available camptothecin derivatives.
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PMID:Potent topoisomerase I inhibition by novel silatecans eliminates glioma proliferation in vitro and in vivo. 1051 2

Intraperitoneal chemotherapy has been the treatment for peritoneal seedings. Most of the anti-tumor agent administered intraperitoneally is absorbed from visceral peritoneum, gets into the portal vein system and reaches the liver. Theoretically, intraperitoneal administration of anti-tumor agents must show equivalent effects on the liver metastasis to portal vein infusion. We compared the efficacy of intraperitoneal and intravenous administration of 5-FU, CDDP and CPT-11, using colon 26 mouse liver metastasis model. Intraperitoneal administration of 5-FU or CPT-11 was statistically superior to intravenous administration to diminish the liver metastatic deposits. CDDP experiment did not show a statistical difference, but the superiority intraperitoneal administration was recognized. Intraperitoneal administration of anti-tumor agents is more effective for not only peritoneal seedings but also liver metastases than intravenous administration. Intraperitoneal chemotherapy might be an effective adjuvant chemotherapy for gastrointestinal malignancies.
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PMID:[Experimental study on intraperitoneal and intravenous administration of anti-tumor agents for liver metastasis]. 1056 Mar 94

We describe a patient with highly refractory malignant lymphoma who died of hepatic tumor rupture following treatment with irinotecan (CPT-11). This 60-year-old man with non-Hodgkin's lymphoma (diffuse large B-cell lymphoma) demonstrated disease recurrence in the liver and the vertebrae following high-dose chemotherapy and autologous hematopoietic stem cell transfusion. He was treated with CPT-11 at a dose of one third of the conventional dose used for non-Hodgkin's lymphoma in Japan. The tumor in the liver markedly decreased in size but then ruptured. Although pathologic hepatic tumor rupture is a rare complication in patients with malignant lymphoma of the liver, this case demonstrates that hepatic tumor rupture may occur in refractory malignant lymphomas that reveal extensive degradation by this new, effective salvage therapy.
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PMID:Hepatic tumor rupture following effectual treatment with irinotecan in a patient with highly refractory malignant lymphoma. 1056 11

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) can induce apoptosis in a wide variety of transformed human cells in vitro. In this study, the antitumor activity of recombinant TRAIL was analyzed in mice bearing human colon carcinoma tumors. We found that these tumors displayed a differential sensitivity to TRAIL in vivo that paralleled their susceptibility to TRAIL-induced apoptosis in vitro. Treatment of TRAIL-sensitive tumors 3 days after tumor challenge resulted in a dose-dependent inhibition of growth and the elimination of tumors in many mice. Colon carcinoma cell lines could be further sensitized to TRAIL-induced apoptosis in vitro by the addition of the chemotherapeutic agent camptothecin. Moreover, the combination of TRAIL and CPT-11, a water-soluble analogue of camptothecin, greatly enhanced the antitumor activity of TRAIL in vivo. TRAIL plus CPT-11 treatment of both 3- and 10-day established TRAIL-sensitive tumors resulted in both a significant inhibition of tumor growth and a high proportion of complete tumor regressions. Treatment of TRAIL-resistant tumors with TRAIL and CPT-11 dramatically slowed tumor growth and induced a transient tumor regression. These data demonstrate that TRAIL alone is a potent antitumor agent in vivo, and its activity can be significantly enhanced in combination with the chemotherapeutic agent CPT-11.
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PMID:Tumor necrosis factor-related apoptosis-inducing ligand's antitumor activity in vivo is enhanced by the chemotherapeutic agent CPT-11. 1062 6

Irinotecan (CPT-11) and carboplatin have broad anti-tumor activities. We conducted a Phase I study of CPT-11 combined with carboplatin in previously untreated solid cancers, especially advanced lung cancer. The aim of the study was to determine the maximum tolerated dose (MTD) and the dose-limiting toxicities in this regimen. In addition, we prospectively evaluated the Chatelut formula for predicting carboplatin clearance. Patients with advanced cancer were treated with CPT-11 (days 1, 8, and 15) and carboplatin (day 1) of a fixed-target area under the concentration-time curve (AUC) of 5 mg x min/ml. Carboplatin dose was determined by multiplying the AUC by the clearance predicted using the Chatelut formula. The CPT-11 dose was escalated from 40 mg/m2 to the MTD by 10 mg/m2. A total of 27 patients, 26 lung cancer patients and 1 colon cancer patient, were enrolled in this study. Dose-limiting leukoneutropenia, thrombocytopenia, and diarrhea, including one treatment-related death, were observed at 60 mg/m2 CPT-11, indicating that this level was the MTD. In 11 patients, the actual AUCs of carboplatin almost achieved the target AUC of 5. Fifteen (60%) of 25 evaluable patients showed an objective response, with an 85% response rate [11 of 13 patients (complete response, 31%; partial response, 54%)] in small cell lung cancers and a 36% response rate (4 of 11 patients) in non-small cell lung cancers. Neutropenia, thrombocytopenia, and diarrhea were the dose-limiting toxicities in this regimen. CPT-11 (50 mg/m2) under the carboplatin target AUC of 5 using the Chatelut formula was the recommended dose for further Phase II study, and this regimen seems to be active for small cell lung cancer.
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PMID:Phase I study of irinotecan combined with carboplatin in previously untreated solid cancers. 1063 26

Despite the generally high cure rate in patients with metastatic testicular cancer, 20% to 30% of treated patients will become candidates for salvage chemotherapy. We reviewed the recent salvage chemotherapy trials of refractory diseases. CPT-11 is a new derivative of camptothecin and has activity in a variety of solid tumors. We evaluated the antitumor effect of combination chemotherapy using CDDP and CPT-11 against refractory testicular cancer. Fourteen patients who failed to achieve complete remission with salvage chemotherapy were treated with combination chemotherapy with CPT-11 and CDDP or 254-S (nedaplatin) as third line chemotherapy. Six patients remain alive and disease-free and 5 patients died of disease. The combination of CPT-11 and either CDDP or nedaplatin was significantly more effective than other salvage therapy regimens such as VIP. Paclitaxel, ifosfamide, etoposide regimens were also effective in patients with refractory testicular tumors. We concluded that these combination regimens demonstrated significant activity against refractory testicular tumor and further investigation is warranted.
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PMID:[The salvage chemotherapy for refractory testicular cancer with novel anticancer agents]. 1063 49


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