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

Malignant melanoma is increasing in frequency at a rapid rate in the United States. Metastatic disease is chemoresistant with DTIC considered the most active single agent. CI-980 is a synthetic mitotic inhibitor that blocks the assembly of tubulin and microtubules. It has shown cytotoxic activity against a broad spectrum of murine and human tumor cell tines. CI-980 can cross the blood brain barrier, is effective when given orally or parenterally, and is active against multidrug resistant cell lines overexpressing P-glycoprotein. In this trial, patients with disseminated melanoma with measurable disease, SWOG performance status of 0-1, no prior chemotherapy or immunotherapy for metastatic disease, and adequate hepatic and renal function, were enrolled. Treatment with CI-980 was given by 72 h continuous i.v. infusion at a dose of 4.5 mg/m2/day, days 1-3 every 21 days. Twenty-four patients were registered on this study with no patients ineligible. They ranged in age from 33-78 with performance status of 0 in 15 patients and 1 in 9 patients. Nineteen patients had visceral disease with 12 having liver involvement. There were no confirmed responses. The overall response rate was 0% (95% CI 0%-14%). The median overall survival is eleven months (95% CI 4-14 months). The most common toxicities were hematologic and consisted of leukopenia/granulocytopenia and anemia, with nausea/vomiting and malaise/fatigue/weakness also frequent. CI-980 administered at this dose and schedule has insufficient activity in the treatment of disseminated malignant melanoma to warrant further investigation.
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PMID:Phase II trial of CI-980 in patients with disseminated malignant melanoma and no prior chemotherapy. A Southwest Oncology Group study. 1156 81

In 45 osteosarcoma patients, mean age 18 (4-61) years and followed for 14 (5-48) months, we studied the sensitivity to doxorubicin as well as P-glycoprotein expression, and compared these with the extent of tumour necrosis following chemotherapy. Doxorubicin assay was positive in 37 patients in whom necrosis induced by chemotherapy was good in 20 and poor in 17. Metastases developed in nine patients. In eight patients in whom doxorubicin assay indicated tumour resistance, chemonecrosis was poor and all developed pulmonary metastases. P-glycoprotein was studied in pre-treatment biopsies and post-treatment resection specimens. Its expression was positive in 16 patients in whom the necrosis induced by chemotherapy was good in four and poor in 12. In 29 patients with negative P-glycoprotein expression, necrosis was good in 16 and poor in 13. The doxorubicin sensitivity had a high correlation with chemonecrosis (P=0.006) and the incidence of metastases (P<0.001). However, P-glycoprotein expression at the time of diagnosis did not correlate statistically with chemonecrosis (P=0.066). Doxorubicin sensitivity prior to treatment is a better determinant of the response to chemotherapy and clinical outcome than is the P-glycoprotein expression.
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PMID:Clinical significance of P-glycoprotein immunohistochemistry and doxorubicin binding assay in patients with osteosarcoma. 1179 58

Malignant brain tumors and brain metastases present a formidable clinical challenge against which no significant advances have been made over the last decade. Multidrug resistance (MDR) is one of the main factors in the failure of chemotherapy against central nervous system tumors. The MDR1 gene encoding P-glycoprotein (P-gp), a drug efflux pump which plays a significant role in modulating MDR in a wide variety of human cancers, is highly expressed in the blood-brain barrier (BBB). The BBB controls central nervous system exposure to many endogenous and exogenous substances. The exact molecular mechanisms by which the BBB is involved in the resistance of brain tumors to chemotherapy remain to be identified. The purpose of this review is to summarize reports demonstrating that P-gp, one of the most phenotypically important markers of the BBB, is present in primary brain tumors and thus plays a crucial role in their clinical resistance to chemotherapy.
Cancer Metastasis Rev 2001
PMID:Multidrug resistance in brain tumors: roles of the blood-brain barrier. 1183 41

When P-glycoprotein (PGP) was first identified as a direct mediator of multidrug resistance (MDR) a great deal of excitement was generated as scientists and clinicians anticipated the ability to successfully treat previously refractory cancers by blocking this drug efflux pump. More than twenty years later there is still minimal evidence that inhibiting PGP will have widespread impact on the chemosensitivity of human tumors. Yet, we know that PGP is over-expressed in many cancers, is associated with poor prognosis in certain tumor types and, if functional, will certainly reduce the accumulation of many common anticancer drugs inside tumor cells exhibiting elevated PGP levels. Similar situations have arisen more recently for other potential mediators of chemosensitivity such as the apoptosis antagonist protein Bcl-2. Bcl-2 has been linked to drug resistance and poor patient prognosis in numerous studies. There has been a great deal of interest in blocking expression or function of this protein to increase the susceptibility of tumor cells to apoptotic stimuli such as chemotherapy. However, preclinical and clinical evidence supporting this approach as a unilateral means of significantly enhancing the response of tumors to chemotherapy is limited. In view of these examples, it would appear likely that similar caveats will be experienced in the future as new molecular targets are identified for potential MDR reversal. Given the ever increasing evidence of genetic diversity in cancer development and progression, it should not be surprising that the development of MDR is also complex and heterogeneous. Consequently, it should also not be surprising that solutions to this problem are unlikely to arise from interventions aimed at any single resistance mechanism. These concepts suggest that new approaches to addressing the various molecular and pharmacological features associated with MDR will be necessary in order to make significant in-roads into improving the clinical activity of current and future anticancer agents. This review summarizes many of the current directions being taken to overcome MDR and how liposomal drug delivery systems may play an important role in achieving this aim.
Cancer Metastasis Rev 2001
PMID:The role for liposomal drug delivery in molecular and pharmacological strategies to overcome multidrug resistance. 1183 52

The seminal discovery in 1988 that selective protein kinase C (PKC) activators induce multidrug resistance (MDR) in human cancer cells spawned several years of intensive investigations; these studies were primarily directed at the question of whether isozyme-selective PKC antagonism could reverse MDR phenotypes produced in cancer cells by P-glycoprotein and other ATP-binding cassette (ABC) transporters. The first section of this commentary provides a succinct overview of those studies. In the second section, we evaluate why the enthusiasm for studies of the involvement of PKC in transport-related drug resistance is currently diminished, and we offer an assessment of whether the PKC/MDR field should be revisited. The final section of the commentary highlights recent developments in studies of PKC targeting in experimental cancer therapeutics, which continues to be a vibrant field. Highlights include the sensitization of cancer cells to radiation- and drug-induced apoptosis by PKC inhibition.
Cancer Metastasis Rev 2001
PMID:Prospects for targeting protein kinase C isozymes in the therapy of drug-resistant cancer--an evolving story. 1183 53

Resistance to chemotherapy significantly affects the treatment results in various cancers. Multidrug resistance caused by P-glycoprotein expression is now widely studied in human malignancies. We present the results of P-glycoprotein expression examination in 91 tumor tissue samples obtained from children treated for different malignant tumors in the Dept. of Pediatric Oncology, Prague. The correlation between the level of P-glycoprotein expression and tumor histology, clinical outcome, use of therapy, relapse rate and metastatic disease was made. P-glycoprotein expression was found significantly more frequent in soft tissue sarcomas, neuroblastomas, and hepatoblastomas, and generally in disseminated disease. On the contrary, a high expression of P-glycoprotein was not found in malignant brain tumors and nephroblastomas. The data strongly support the possibility that the percentage of P-glycoprotein expressing cells in selected tumors (soft tissue sarcomas, neuroblastomas), may have a clinical importance.
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PMID:Significance of P-glycoprotein expression in childhood malignant tumors. 1194 40

Both 5-fluorouracil and doxorubicin are commonly used agents in chemotherapy of gastric cancer in adjuvant setting as well as metastatic disease. In a variety of malignancies, high expression of multidrug resistance-associated protein1 and P-glycoprotein has been associated with resistance to doxorubicin, whereas 5-fluorouracil resistance has correlated with the level of thymidylate synthase expression. We evaluated the expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase using immunohistochemistry in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection and investigated the association between their expression and clinicopathologic characteristics including prognosis of the patients. While high expression (> or =5% of tumour cells positive) of multidrug resistance-associated protein1 and P-glycoprotein was observed in 70 patients (68%) and 42 patients (41%), respectively, 65 patients (63%) had primary tumours with high expression (> or =25% of tumour cells positive) of thymidylate synthase. There was a significant association between multidrug resistance-associated protein1 and P-glycoprotein expression (P<0.0001) as well as P-glycoprotein and thymidylate synthase expression (P<0.0001). High multidrug resistance-associated protein1 and P-glycoprotein expressions were associated with well and moderately differentiated histology (P<0.0001 and P=0.03, respectively) and intestinal type (P<0.0001 and P=0.009, respectively). High multidrug resistance-associated protein1 expression correlated with lymph node metastasis (P=0.037), advanced stage (P=0.015), and older age (P=0.021). Five-year disease-free survival and overall survival of total patients were 55.2% and 56.2%, respectively, with a median follow-up of 68 months. There were no significant differences in disease-free survival and overall survival according to the expression of multidrug resistance-associated protein1 (P=0.902 and P=0.975, respectively), P-glycoprotein (P=0.987 and P=0.955, respectively), and thymidylate synthase (P=0.604 and P=0.802, respectively). Concurrent high expression of these proteins (high multidrug resistance-associated protein1/P-glycoprotein, high multidrug resistance-associated protein1/thymidylate synthase, high P-glycoprotein/thymidylate synthase) did not correlate with disease-free survival or overall survival. Even high expression of all three proteins was not associated with poor disease-free survival (P=0.919) and overall survival (P=0.852). In conclusion, high expression of multidrug resistance-associated protein1, P-glycoprotein, and thymidylate synthase did not predict poor prognosis of gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy. A larger study including patients treated with surgical resection alone would be necessary.
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PMID:Expression of multidrug resistance-associated protein1,P-glycoprotein, and thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection. 1208 7

Our purpose was to determine the expression of the drug resistance factors multidrug resistance protein (MRP1), lung resistance protein (LRP) and P-glycoprotein (Pgp) in breast carcinoma patients treated with preoperative chemotherapy. We have studied the expression of these proteins in breast carcinomas by immunohistochemistry both prior (n = 80) and after (n = 68) preoperative chemotherapy and compared their expression with response to preoperative chemotherapy. In paired samples prior and after chemotherapy expression of drug resistance factors was significantly lower in prechemotherapy samples as compared with postchemotherapy specimens. This was observed for MRP1 (62% vs. 88%, P < 0.001), LRP (65% vs. 97%, P < 0.001) and Pgp (55% vs. 100%, P < 0.001). Prechemotherapy expression of MRP1 was more frequently observed in patients with distant metastases than in those without (50% vs. 8%, P = 0.02). No associations were observed between LRP expression and clinical parameters. Pgp expression was more frequently detected in lobular carcinomas than in ductal carcinomas (93% vs. 46%, P = 0.001) and in patients with positive lymph nodes than in patients with negative lymph nodes (65% vs. 31%, P = 0.008) but was independent of other clinical parameters. No significant associations were found between the prechemotherapy or postchemotherapy expression of either of these three proteins and response to preoperative chemotherapy. However, prechemotherapy MRP1 expression was significantly associated with shorter progression-free survival of the patients (P = 0.02), whereas no such associations were observed for either LRP or Pgp. In conclusion, preoperative chemotherapy increases the expression of MRP1, LRP and Pgp. Response to chemotherapy is not associated with pre- or postchemotherapy expression levels of these drug resistance proteins but time to progression may be influenced by prechemotherapy MRP1 expression.
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PMID:Expression of MRP1, LRP and Pgp in breast carcinoma patients treated with preoperative chemotherapy. 1457 57

P-glycoprotein overexpression is an important adverse prognostic marker for osteosarcoma (OS) patients, which is associated with higher risk for developing metastases as a consequence of the limited responsiveness to standard treatments of P-glycoprotein overexpressing OS cells. The use of cytokines has been advocated as a possible therapeutic approach to overcome multidrug resistance (MDR), being active on cell lines that are resistant to conventional drugs. In this study, we evaluated in vitro effects of interferons (IFNs) on MDR P-glycoprotein overexpressing OS cells. Type I IFNs, but not IFNgamma, showed tangible inhibitory effects on OS cell growth, which were higher in MDR cell lines compared to parental cells. The higher sensitivity of P-glycoprotein overexpressing cells to Type I IFNs correlates with higher expression of the activator of the transcription (STAT)-2 and (STAT)-3, two intracellular mediators of the IFNalpha and IFNbeta signaling pathways, whereas no differences were observed with respect to the expression or activation of the Type I IFN receptor and STAT-1. Exposure of OS MDR cells to Type I IFN decreased the expression of P-glycoprotein. This effect resulted in a significantly increased chemosensitivity of MDR cells to doxorubicin. Therefore, our data support the use of IFNalpha or IFNbeta in the treatment of osteosarcoma patients who overexpress P-glycoprotein in their primary tumors, and respond insufficiently to current therapeutic regimens.
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PMID:Effectiveness of Type I interferons in the treatment of multidrug resistant osteosarcoma cells. 1471 13

The thiocarbamate alcoholism drug disulfiram blocks the P-glycoprotein extrusion pump, inhibits the transcription factor nuclear factor-kappaB, sensitizes tumors to chemotherapy, reduces angiogenesis, and inhibits tumor growth in mice. Thiocarbamates react with critical thiols and also complex metal ions. Using melanoma as the paradigm, we tested whether disulfiram might inhibit growth by forming mixed disulfides with critical thiols in a mechanism facilitated by metal ions. Disulfiram given to melanoma cells in combination with Cu2+ or Zn2+ decreased expression of cyclin A and reduced proliferation in vitro at lower concentrations than disulfiram alone. In electrophoretic mobility shift assays, disulfiram decreased transcription factor binding to the cyclic AMP-responsive element in a manner potentiated by Cu2+ ions and by the presence of glutathione, suggesting that thiocarbamates might disrupt transcription factor binding by inducing S-glutathionylation of the transcription factor DNA binding region. Disulfiram inhibited growth and angiogenesis in melanomas transplanted in severe combined immunodeficient mice, and these effects were potentiated by Zn2+ supplementation. The combination of oral zinc gluconate and disulfiram at currently approved doses for alcoholism also induced >50% reduction in hepatic metastases and produced clinical remission in a patient with stage IV metastatic ocular melanoma, who has continued on oral zinc gluconate and disulfiram therapy for 53 continuous months with negligible side effects. These findings present a novel strategy for treating metastatic melanoma by employing an old drug toward a new therapeutic use.
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PMID:Disulfiram inhibits activating transcription factor/cyclic AMP-responsive element binding protein and human melanoma growth in a metal-dependent manner in vitro, in mice and in a patient with metastatic disease. 1536 99


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