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)

The purpose of the present study was to evaluate cytotoxic agents active for mucinous adenocarcinoma of the ovary (MACO) which is considered to be intrinsically platinum-resistant. We first conducted in vitro chemosensitivity tests assessing cytotoxic activities of various anti-cancer agents against MACO using a cell line, designated OMC-3, established from ascites of a patient with histologically pure MACO. The most active single agent was SN-38 (active substance of CPT-11 in vivo). The second most potent agent was mitomycin-C (MMC) followed by doxorubicin (DOX). In vivo chemo-sensitivity test of agents on OMC-3 transplanted into Balb/c nude mice demonstrated that MMC was most potent, followed by DOX. Moreover, a combination of CPT-11 and MMC exhibited the highest anti-tumor activity in this animal model. Cisplatin was found to be ineffective in both the in vitro and in vivo experimental system. Clinical trial with a combination of MMC and CPT-11 are justified in patients with MACO.
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PMID:Cytotoxic agents active against mucinous adenocarcinoma of the ovary. 945 1

The present study evaluated the plasma pharmacokinetics of irinotecan (CPT-11) and its effects against a human neuroblastoma in xenograft, given by different administration routes. One-third of the LD50 was administered either intraperitoneally (59 mg/kg mouse weight (MW)) or orally (404 mg/kg MW) to nude mice. The plasma levels of CPT-11 and its active metabolite SN-38 decreased rapidly when CPT-11 was administered intraperitoneally, but remained relatively high for 4-8 h after oral administration. Then, a human neuroblastoma xenograft was inoculated in another set of 21 nude mice. When the estimated tumor weight reached 150-200 mg, CPT-11 was administered in the total LD50 either intraperitoneally or orally in three doses at 4-day intervals (q4d x3) to the mice in each experimental group. Oral administration was found to be superior to intraperitoneal injection in terms of tumor inhibition and to be an effective route for CPT-11 administration in the treatment of human neuroblastoma in nude mice.
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PMID:Oral versus intraperitoneal administration of irinotecan in the treatment of human neuroblastoma in nude mice. 950 Jan 86

To evaluate the concept that in vivo transfer of the human carboxylesterase gene will confer sensitivity of a solid tumor to the prodrug CPT-11 (irinotecan), we constructed an adenovirus vector (AdCMV.CE) carrying the human carboxylesterase gene driven by the cytomegalovirus (CMV) promoter, infected A549 human lung adenocarcinoma cells in vitro and in vivo, and evaluated cell growth over time. AdCMV.CE produced a functional carboxylesterase protein in A549 cells in vitro and in vivo as evidenced by ability of lysates from the infected cells to convert CPT-11 to its active metabolite SN-38. The AdCMV.CE vector effectively suppressed A549 cell growth in vitro in the presence of CPT-11. Cell mixing studies demonstrated that when as few as 10% of cells expressed the human carboxylesterase gene, there was bystander growth suppression in the presence of CPT-11. Consistent with these in vitro observations, when AdCMV.CE was directly injected into established subcutaneous A549 tumors in nude mice receiving CPT-11, there was 35% reduction in tumor size at day 27 compared to controls, and a 41% reduction at day 34 (P < 0.01, both comparisons to controls). Similar observations were made with the cell line H157 and HeLa. These observations suggest that local gene transfer of the human carboxylesterase gene and concomitant local administration of CPT-11 may have potential as a strategy for control of the growth of solid tumors.
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PMID:In vivo human carboxylesterase cDNA gene transfer to activate the prodrug CPT-11 for local treatment of solid tumors. 954 11

A 71-year-old woman presented with an abdominal mass and ascites and was subsequently admitted to our hospital in June 1995. Further examination revealed that the mass was malignant and, as a result, surgery was indicated. However, the mass demonstrated widespread peritoneal dissemination, which therefore could not be resected, and pathological findings suggested a malignant peritoneal mesothelioma. The patient showed a remarkable response to combined chemotherapy with an accompanying intraperitoneal injection of cisplatin and etoposide and an intravenous injection of caffeine. However, owing to side effects, this regimen was discontinued. The patient was administered a combination drug of uracil and tegafur (UFT) in addition to intraperitoneal injection of cisplatin as an outpatient. By the 223rd day after surgery, the tumor mass and ascites had completely disappeared according to the CT. Hence chemotherapy was judged to have resulted in complete remission. Such a marked response to chemotherapy is rare in an advanced malignant peritoneal mesothelioma such as the present case. Eight months later, the tumor recurred in the pleura. Another regimen of chemotherapy with cisplatin and CPT-11 was performed. However, this treatment proved ineffective. The patient subsequently died of respiratory failure in January 1997 due to the mesothelioma. This is a case report of complete remission of malignant peritoneal mesothelioma by combined chemotherapy.
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PMID:A case of malignant peritoneal mesothelioma showed complete remission with chemotherapy. 954 32

Two major obstacles in the treatment of patients with central nervous system malignancies are drug resistance and host toxicity. The goal of combination chemotherapy is to achieve therapeutic effects that are more favorable than using a single drug alone, but without an increase in normal organ toxicity. The study reported here examined the combination of a topoisomerase I inhibitor, irinotecan (CPT-11), with three different alkylating agents: 1,3-bis(2-chloroethyl)-1-nitrosourea, busulfan, and cyclophosphamide. We evaluated the antitumor effects of these three combinations against a panel of human tumor xenografts derived from central nervous system malignancies, including adult high-grade gliomas (D-54 MG, D-245 MG) and a childhood ependymoma (D-612 EP). In replicate experiments, the alkylating agents were given on day 1 in doses varying from 10% to 75% of the dose lethal to 10% of the animals, and CPT-11 was given on days 1-5 and 8-12 in doses varying from 10% to 100% of the dose lethal to 10% of the animals. The antitumor effects of the various combinations ranged from less than additive (7.61 days below additive with 0.5 CPT-11 + 0.75 cyclophosphamide in D-54 MG) to statistically significant (P < 0.001) supraadditive effects (18.80 days above additive with 0.5 CPT-11 + 0.5 1,3-bis(2-chloroethyl)-1-nitrosourea in D-54 MG). These studies show that the combination of the topoisomerase inhibitor CPT-11 and alkylating agents may increase the antitumor effect in some cases well above additive with no increase in host toxicity (0/10 deaths in both experiments cited above) and should be considered for combination chemotherapy of central nervous system malignancies.
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PMID:Enhancement of irinotecan (CPT-11) activity against central nervous system tumor xenografts by alkylating agents. 955 93

We have examined the efficacy of liposomalization and polyethyleneglycol (PEG) modification of liposomes on the antitumor activity, side-effects and tissue distribution of irinotecan hydrochloride (CPT-11). PEG-liposome was confirmed to elevate the plasma circulation of CPT-11 and SN-38 (active metabolite) concentrations. The tumor accumulation of CPT-11 and SN-38 was increased by the PEG-modified liposomes. The antitumor activity of CPT-11 increased due to the elevated tumor distribution of CPT-11 and SN-38 levels by the PEG-modified liposomes. In the tumor, CPT-11 was converted to SN-38. Thus, it is considered that passive targeting to the tumor by liposomalization elevated the SN-38 level in the tumor especially and increased the antitumor activity of CPT-11. Furthermore, intestinal disorder, a side toxicity of CPT-11, decreased dependent on the CPT-11 and SN-38 concentrations in the bile by liposomalization. Although the liposomes induce improved tissue distribution of the prodrug, the tissue distribution of active metabolites does not always improve. However, CPT-11-entrapped liposome was useful, as CPT-11 is converted to SN-38 in the tumor. These results suggested that the usefulness of CPT-11 could be extended.
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PMID:Effect of liposomalization on the antitumor activity, side-effects and tissue distribution of CPT-11. 961 64

Most clinical drug regimens for irinotecan (CPT-11 [Camptosar]) have been empirically based on classic in vivo pharmacokinetic and pharmacodynamic considerations. We propose an alternative approach that attempts to provide a rationally designed schedule of irinotecan administration based on preclinical data. HL60 cells grown in suspension or as subcutaneously implanted solid xenografts in nude mice served as in vitro and in vivo models to rest the activity of irinotecan or its active metabolite, SN-38. For SN-38, within an effective drug concentration range, scheduling drug administration based on duration of DNA synthesis inhibition significantly potentiated cell kill in vitro, and increasing drug concentrations at suboptimal scheduling did not result in additive cell kill. These data suggested that even though high drug doses may be attainable in vivo, they may not be required to achieve maximum antitumor activity. To test this hypothesis, a sensitive in vivo model to test the toxicity and antitumor activity of CPT-11 is required, which is provided in the human myeloid HL60 xenograft model grown in nude mice. In this model, CPT-11 at a dose 50 mg/kg, daily x5 (MTD) achieved 100% complete tumor regression. This model should be useful to test the hypothesis that for irinotecan, administration of a minimum effective dose (MED) at an optimal schedule can achieve maximum antitumor activity and should therefore prevail over the classic approach of administering the MTD.
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PMID:Rational design of irinotecan administration based on preclinical models. 972 87

The unique mechanism of action of irinotecan (CPT-11 [Camptosar]), topoisomerase I inhibition, together with the results of preclinical studies, suggest that the drug's antitumor and toxicologic effects may be schedule-dependent. To further explore this possibility, we reviewed the initial phase I studies of various administration schedules that have been conducted in Japan, France, and the United States. This review showed toxicities to be fairly consistent across dosing schedules, although the severity and extent of diarrhea and neutropenia differed somewhat. The institution of intensive loperamide therapy and perhaps myeloid growth factors may have allowed for further dose escalation on some schedules, although it is unclear whether dosing intensity should be pursued without regard to dosing frequency. Preliminary antitumor activity of irinotecan noted in a study of leukemia and lymphoma supports the theory that the drug may exhibit schedule-dependent antitumor activity. The results of these early studies of irinotecan should be taken into account when designing subsequent trials of the agent alone or in combination with other chemotherapeutics in specific tumor types.
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PMID:Irinotecan: a review of the initial phase I trials. 972 88

It has been hypothesized that intratumoral thymidylate synthase (TS) gene expression might be used to select therapy for patients with disseminated colorectal cancer. We recently reported the results of a clinical trial in 46 patients with disseminated or recurrent colorectal cancer testing whether expression of TS within the primary tumor, as assessed by quantitative polymerase chain reaction (PCR) methodology, would predict the responsiveness of that cancer of fluoropyrimidine-based therapy. This trial demonstrated that intratumoral TS/beta-actin messenger RNA (mRNA) ratio can accurately predict which metastatic colorectal tumors will be resistant to a leucovorin-modulated 5-FU infusion and which have a high likelihood of responding to such a regimen. Results of other studies of adjuvant therapy in gastric cancer and colorectal cancer also indicated that TS expression within the tumor is predictive of response of 5-FU-based therapy. It may be possible to use this parameter prospectively to decide which patients should receive fluorinated pyrimidine therapy: Patients whose tumors express low TS levels would be likely to benefit from such therapy, whereas limited preliminary data suggest that patients whose tumors express high TS levels may benefit from irinotecan (CPT-11[Camptosar]).
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PMID:Thymidylate synthase as a predictor of response. 972 90

Irinotecan (CPT-11 [Camptosar]) is currently approved for use as a second-line agent in the treatment of metastatic colorectal cancer. Phase II studies have also shown substantial single-agent activity of irinotecan in the first-line treatment of metastatic colorectal cancer. Response rates appear to be similar to those seen with standard first-line regimens, although direct randomized comparisons have not yet been reported. In the absence of definitive data showing irinotecan to be superior, its routine use as a single agent in the first-line treatment of colorectal cancer may be hard to justify, given the significant cost differential between irinotecan and current standard first-line regimens. Studies exploring combinations of irinotecan with fluorouracil may identify a first-line role for these combination regimens. Also, use of specific molecular markers may permit the identification of selected patients with tumor characteristics that would specifically favor consideration of upfront irinotecan monotherapy.
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PMID:Irinotecan in the first-line treatment of colorectal cancer. 972 92


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