Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0027627 (metastases)
 103,950 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have shown previously that tumor cell variants able to form experimental metastases can be generated stochastically in mouse cell lines at high rates and that, in B16 melanoma cell lines, resistance to drugs is associated with metastatic ability. Recently, we reported on the ability of two lines of KHT fibrosarcoma cells derived from individual experimental lung metastases to generate metastatic variants. The KHT 35LI cell line maintained a relatively stable high metastatic ability while the parallel line KHT 3LIc possessed a high metastatic ability when first cultured from the lung but rapidly lost this ability and became a line with a metastatic ability similar to the KHT parental line. Subsequent rate analysis indicated that the rate of generation of metastatic variants was higher for KHT 35LI cells compared to KHT 3LIc or KHT parental cells. Here we examined the ability of these two fibrosarcoma cell lines to generate variants resistant to the drugs methotrexate (MTX) and N-(phosphonacetyl)-L-aspartate (PALA). We observed that the highly metastatic KHT 35LI cell line is more resistant to these two drugs than the KHT 3LIc or the parental KHT cell lines. Cloning studies indicated that the likely reason for this increased resistance is that the KHT 35LI cell line generates variants resistant to a given concentration of MTX or PALA at higher rates than the KHT 3LIc or KHT parental cell lines. Since resistance to MTX and PALA usually arises from gene amplification, the results suggest that KHT 35LI cells possess increased ability to amplify their DNA. The association between the rates of generation of both drug-resistant and metastatic variants supports the hypothesis that the mechanism of gene amplification may be involved in the generation of both phenotypes.
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PMID:Drug resistance in KHT fibrosarcoma cell lines with different metastatic ability. 291 Aug 23

Carrier-based formulations of cytotoxic agents may be highly efficacious for intracavitary therapy of malignancies which reside in or metastasize to the peritoneal cavity. N-(Phosphonacetyl)-L-aspartic acid (PALA) is a transition-state inhibitor of aspartate transcarbamylase which has shown enhanced activity against several cell lines upon encapsulation in liposomes. We have examined the growth inhibitory effects of PALA-containing liposome formulations against four human ovarian cancer cell lines (Ovcar-3, Hey-1b, A90, and A121a) that have significantly different growth characteristics. With the optimal liposome formulation defined in the present studies, the potency of encapsulated PALA was 22- to 570-fold greater than that of free PALA, depending on the cell line. Control liposomes containing buffer, rather than PALA, did not inhibit cell growth. Fluorescence studies of liposome-cell interaction suggest that high liposome negative surface charge density and high phase transition temperature increase both cellular association and retention of liposome contents. Briefer exposure of tumor cells to treatment accentuates the advantage of liposome formulations; on Hey-1b cells, the cytostatic effect of 1-hr exposure to PALA-liposomes is 900-fold greater than is the equivalent exposure to free PALA. The considerable increase in in vitro potency of PALA-liposome formulations, coupled with potential pharmacokinetic advantages in vivo (i.e., intraperitoneal retention of liposome-associated drug versus rapid clearance of free PALA), suggests the possibility of enhanced antitumor activity of liposome-encapsulated PALA for both single-agent and combination chemotherapy.
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PMID:Modulation of human ovarian tumor cell sensitivity to N-(phosphonacetyl)-L-aspartate (PALA) by liposome drug carriers. 827 4

A total of 55 patients with measurable colorectal metastatic carcinoma were studied to evaluate the impact on toxicity, response, and survival of protracted venous infusion (PVI) 5-FU 200 mg/m2 per day with Cis-DDP 80 mg/m2 or carboplatin 300 mg/m2 every 3 weeks, 1-hour infusion. Patients received continuous uninterrupted therapy until there were signs or symptoms of toxicity. Both 5-FU and cisplatin were withheld when patients experienced grade II stomatitis and diarrhea, severe nausea or vomiting not controlled by standard antiemetic therapy, and clinically significant hand-foot syndrome. The toxicity was neurological (20% grade 2 and 3) hematological (13% grade 2) and dermatological (11% grade 2). The overall response (CR+PR) was 24% with a median survival of 13 months. The results of our study show that there is no improvement in response rate, response duration or survival compared with historical trials. However, this study does confirm the valuable palliative role of the protracted 5-FU infusion treatment. Colorectal carcinoma is one of the most common neoplasms in Western societies, being second only to lung cancer as a cause of death from malignancy. The management of nonmetastatic primary disease in surgical, with adjuvant chemotherapy for those at high risk of relapse. However, for those with metastatic disease at diagnosis or recurrent disease after resection, cytotoxic chemotherapy is the treatment of choice and fluorouracil (5-FU) is the most active cytotoxic agent in this disease, with a response rate of approximately 20%. Efforts to improve the response rate have focused on the use of agents to modulate 5 FU. The Southwestern Oncology Group (SWOG) study reported by Leichman et al. (1) and a study from the United Kingdom by Hill et al. (2) compared conventional FU to modulated FU and found no improvement in response rate or survival. In the SWOG study, two different schedules of bolus FU and LV were compared with bolus FU alone and to continuous infusion FU administered alone or modulated by LV or PALA. In this study, the results obtained with bolus FU were superior to most of the studies in the literature: The response rate was 26%, and the median survival was 14 months. The high- and low-dose LV and FU groups showed response rates and survival similar to bolus FU alone. However, in 12 previously reported randomized studies comparing FU and LV or FU alone, nine reported that the combination of FU and LV produced significant increases in response rates and two reported significant increase in survival (3, 4). Many of these trials used the dose schedules reported in the SWOG trial. Protracted venous infusion (PVI) 5-FU has been shown to have superior efficacy with less toxicity in colorectal cancer when compared to bolus 5-FU and synergy between cisplatin and 5-FU has been demonstrated in vitro. Consequently, we have investigated the efficacy of the combination of bolus cis or carboplatin and PVI 5 FU in 55 patients with advanced colorectal cancer using survival, response rate, symptomatic response, and toxicity as study endpoints.
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PMID:First-line protracted venous infusion fluorouracil with CisDDP or carboplatin in advanced colorectal cancer. 922 28

The current phase III studies of chemotherapy in advanced colorectal cancer include 60% to 85% of patients with the liver as a site of metastatic disease. Within the past 10 years, various modulatory combinations of 5-fluorouracil (5-FU) with agents such as leucovorin, interferon, N-(phosphonacetyl)-L-aspartate (PALA), and methotrexate have produced higher response rates than 5-FU alone. A major seven-arm study, conducted by the Southwestern Oncology Group and reported in 1995, suggested that single-agent, continuous-infusion 5-FU demonstrated the most encouraging results. Nine of 12 reported randomized studies comparing the combination of 5-FU and leucovorin with 5-FU alone report significant increases in response rates; two studies reported significant increases in survival. The meta-analysis project involving 1381 patients confirmed the increase in response rate with the combination (23%) vs. 5-FU alone (11%) but did not demonstrate any significant difference in median survival. The current issues involving 5-FU administration largely concentrate on the best approach (modulation vs. scheduling) and comprehensive evaluation of end points (quality of life, survival, and pharmacoeconomics). The current literature examining quality-of-life issues suggests that 5-FU and low-dose leucovorin produce the best overall improvement in symptoms. Others argue that continuous-infusion scheduling is also associated with a very good quality of life (although the increased cost and morbidity of continuous-infusion administration has to be factored into this consideration). An important phase III study is currently being conducted by the National Cancer Institute of Canada comparing immediate vs. delayed (until symptomatic) chemotherapy in patients with advanced colorectal cancer. Of the new approaches to therapy, perhaps the most immediately applicable are the new thymidylate synthase inhibitors (in particular, Tomudex, which produces a response rate equivalent to that of 5-FU plus leucovorin with less toxicity and a more convenient schedule).
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PMID:Management of hepatic metastases from colorectal cancer: systemic chemotherapy. 983 94

Adenocarcinoma of the pancreas is the cause of 3-4% of cancer related deaths in Italy and over 80% of all patients exhibit advanced disease. Treatment with surgery and chemio-radiotherapy may have meaningful results in resectable and locoregional tumours respectively. Chemotherapy is the treatment of choice in metastatic disease as palliative intent, although pancreatic tumour is considered resistant to treatment with conventional cytotoxicity drugs. Assessment of response of primary tumor is extremely difficult because of its anatomical location and fibrotic reaction around the tumor. Furthermore, medical problems associated with the age of patients, reduced performance status (PS), mainourished conditions, jaundice and pain, limit patients' tolerance and response to chemotherapy. 5-fluorouracil (5-FU) is the most frequently used drug in the treatment of pancreatic cancer with a RR of 28% in the trials performed in mid 1980, while more recently studies have reported a RR of 5-15%. Biochemical modulation of 5-FU by leucovorin, PALA and interferon does not appear to produce better results than 5-FU alone. 5-FU-based combination chemotherapy (FAM, SMF, etc) have shown interesting results in phase II (30-40%), but in a randomized trial the results of combination were similar to 5-FU alone (< 15%). Also, regimens containing platinum gave disappointing results just as the other combinations and cannot be recommended outside prospective clinical trials. When chemotherapy was compared to best supportive care (BSC), the results demonstrated a survival gain. Six studies, comparing chemotherapy versus BSC and 3 trials showed statistically significant difference in survival for patients treated with chemotherapy. Recently, new drugs have been introduced in the treatment of gastrointestinal tumour (gemcitabine, CPT11, raltitrexed, taxanes, etc.). Gemcitabine is a novel nucleoside analogue that has shown a very favourable toxicity profile and RR of 10-15% in advanced pancreatic cancer. Data from a phase II and randomized comparative trials suggest that gemcitabine offers an advantage over 5-FU in terms of improvement of PS and general clinical symptoms. Given the difficulty of accurate tumor measurement in this disease, some authors introduced a novel new end-point to evaluate the response: clinical benefit (CB). In a randomized trial of gemcitabine vs. 5-FU, RR using CB was 23.8 with gemcitabine and 4.8 with 5-FU, this difference was statistically significant with a median survival of 5.6 and 4.4 months, respectively. In conclusion, future studies should focus on phase III trials with gemcitabine, alone or in combination and phase II with new promising drugs. Quality of life, pharmaco-economic studies, CB should be the principal end-point of these studies. All patients with advanced pancreatic cancer should be included in clinical cooperative trials.
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PMID:[Possibilities of palliation in pancreatic cancer]. 1023 81

Gene amplification and microsatellite alteration are useful markers of genomic instability in tumor and transformed cell lines. It has been suggested that genomic instability contributes to the progression of tumorigenesis by accumulating genetic changes. In this study, amplification of the carbamyl-P-synthetase, aspartate transcarbamylase, dihydro-orotase (CAD) gene in transformed and tumorigenic human bronchial epithelial (BEP2D) cells induced by either alpha particles or (56)Fe ions was assessed by measuring resistance to N-(phosphonacetyl)-l-aspartate (PALA). In addition, alterations of microsatellite loci located on chromosomes 3p and 18q were analyzed in a series of primary and secondary tumor cell lines generated in nude mice. The frequency of PALA-resistant colonies was 1-3 x 10(-3) in tumor cell lines, 5-8 x 10(-5) in transformed cells prior to inoculation into nude mice, and less than 10(-7) in control BEP2D cells. Microsatellite alterations were detected in all 11 tumor cell lines examined at the following loci: D18S34, D18S363, D18S877, D3S1038 and D3S1607. No significant difference in either PALA resistance or microsatellite instability was found in tumor cell lines that were induced by alpha particles compared to those induced by (56)Fe ions.
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PMID:Gene amplification and microsatellite instability induced in tumorigenic human bronchial epithelial cells by alpha particles and heavy ions. 1112 Dec 44

Drug resistance is a major obstacle in successful systemic therapy of metastatic cancer. We analyzed the involvement of cell cycle regulatory proteins in eliciting response to N (phosphonoacetyl)-L-aspartate (PALA), an inhibitor of de novo pyrimidine synthesis, in two metastatic variants of human cancer cell line MDA-MB-435 isolated from lung (L-2) and brain (Br-1) in nude mouse, respectively. L-2 and Br-l cells markedly differed in their sensitivity to PALA. While both cell types displayed an initial S phase delay/arrest, Br-l cells proliferated but most L-2 cells underwent apoptosis. There was distinct elevation in cyclin A, and phosphorylated Rb proteins concomitant with decreased expression of bcl-2 protein in the PALA treated L-2 cells undergoing apoptosis. Markedly elevated cyclin A associated and cdk2 kinase activities together with increased E2F1-DNA binding were detected in these L-2 cells. Induced ectopic cyclin A expression sensitized Br-l cells to PALA by activating an apoptotic pathway. Our findings demonstrate that elevated expression of cyclin A and associated kinase can activate an apoptotic pathway in cells exposed to DNA antimetabolites. Abrogation of this pathway can lead to resistance against these drugs in metastatic variants of human carcinoma cells.
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PMID:Elevated cyclin A associated kinase activity promotes sensitivity of metastatic human cancer cells to DNA antimetabolite drug. 2605 63