Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0017638 (glioma)
 30,880 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Use of polymeric drug delivery systems is rapidly becoming an established approach for improvement of cancer chemotherapy. Zoladex, a poly lactide-co-glycolide subcutaneous implant that delivers a luteinizing hormone releasing hormone analog over 28 days, is now the treatment of choice for prostate cancer, and a polyanhydride matrix containing BCNU is currently in phase III evaluation for treatment of glioma multiforme. Soluble polymers were first proposed as targetable drug carriers in the mid-1970s, and although the first conjugates are still at an early stage of development some, e.g. SMANCS (styrene maleic acid-neocarzinostatin) and monomethoxypolyethyleneglycolasparaginase, are now undergoing clinical evaluation and show considerable promise. Polymeric drug delivery systems are usually designed to produce an improved pharmacokinetic profile of an antitumor agent (controlled release) and in addition soluble carriers can achieve either first-order (organ specific) or second-order (tumor specific) drug targeting by virtue of the fact that they are usually administered intravenously and should theoretically access primary and secondary disease. Soluble polymeric carriers have the potential to improve the activity of conventional antitumor agents, peptide and protein drugs, and have recently been used in constructs for delivery of oligonucleotides. With increased awareness that the successful design of a polymeric drug delivery systems can only be achieved with prior consideration of the pathology and stage of the disease, tumor accessibility, biochemistry and cell biology of the target site, choice of appropriate therapeutic agent(s) and understanding of their fundamental mode of action, we have seen the emergence of a number of exciting and potentially more selective antitumor therapies based on polymer technologies. Here, the basic principles for design of soluble polymeric drug delivery systems are explained and illustrated using examples drawn from our studies on the development of N-(2-hydroxypropyl)methacrylamide copolymer conjugates for use in cancer chemotherapy. Those soluble polymeric carriers that are undergoing clinical evaluation are briefly reviewed.
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PMID:Drug-polymer conjugates: potential for improved chemotherapy. 152 99

Estramustine, an estradiol-17 beta and nornitrogen mustard complex, is used in the treatment of advanced prostatic carcinoma. A specific estramustine binding protein (EMBP) is important for its cytotoxic action, and the presence of EMBP has previously been demonstrated in rat and human prostatic cancer tissue. Significant levels of EMBP were detected by radioimmunoassay in human brain-tumor tissue. The EMBP concentrations (expressed as ng/mg protein) in 16 astrocytomas (mean 2.6 ng/mg, range 0.5 to 6.2 ng/mg) and seven meningiomas (mean 5.1 ng/mg, range 0.3 to 9.3 ng/mg) were significantly higher than that found in four samples of epileptic brain (mean 0.7 ng/mg, range 0.5 to 1 ng/mg) and 18 samples of normal brain (mean 0.5 ng/mg, range 0.2 to 1.0 ng/mg). The uptake, metabolism, and antiproliferative effects of the prostatic anticancer agent estramustine have been previously demonstrated in cultured glioma cells. The presence of EMBP may suggest a selective binding and effectiveness in human brain-tumor tissue.
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PMID:Estramustine binding protein in human brain-tumor tissue. 170 87

Estramustine phosphate (EMP), a complex between estradiol-17 beta and nor-nitrogen mustard, commonly used in treatment of prostatic cancer, also exerts marked antiproliferative effects on cultured human malignant glioma cells. The mechanism of action is unknown but has previously been considered to be mediated through non-DNA targets, specifically via the mitotic spindle, and related to the intact estramustine complex. EMP cytotoxicity was studied on the malignant glioma cell line U-251 MG. A dose-dependent increase in DNA strand breaks was demonstrated at EMP-concentrations ranging 10-40 mg/l. The uptake of 86Rb, used as a tracer for potassium to study ion transport and membrane permeability, was reduced after incubation with EMP. The mean decline in 86Rb accumulation by U-251 MG cells was 12, 20 and 32% at EMP concentrations 10, 20 and 40 mg/l respectively. Scanning electron microscopy gave further evidence for cell membrane damage. In conclusion, EMP seems to affect malignant glioma cells on several vital functions and the results indicate the the cytotoxic potential may at least partially be related to effects on DNA and cell membrane.
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PMID:Effects of estramustine on DNA and cell membrane in malignant glioma cells. 195 92

Estramustine, a conjugate of estradiol-17 beta and nor-nitrogen mustard currently used in prostatic cancer, was found to exert a dose-dependent antiproliferative effect on the human malignant glioma cell lines U-251 MG and U-105 MG. At equimolar concentrations the inhibitory effects of the estramustine complex were clearly more pronounced than those of estradiol and nor-nitrogen mustard given alone or in combination. Flow cytometric analyses support the concept that estramustine cytotoxicity is mediated via separate mechanisms. The intact estramustine complex may be important for effects related to microtubule function which add to the cytotoxic potential of the alkylating component.
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PMID:Effects of estramustine and its constituents on human malignant glioma cells. 236 85

The uptake, metabolism and antiproliferative effects of estramustine phosphate, a cytotoxic agent used in prostatic cancer, were investigated in the two human malignant glioma cell lines U-105 MG and U-251 MG. The primary metabolite estramustine had a dose-dependent inhibitory effect on cell proliferation within the concentration range 5-20 micrograms/ml. After incubation with 3H-estramustine phosphate in both cell lines, a progressive uptake of radioactivity was recorded during 24 hours. A significant metabolism of parent estramustine phosphate into estramustine and estramustine, which is a well known part of the metabolic pathway in man, was also demonstrated. In conclusion, certain cultured malignant glioma cells display significant uptake, retention and metabolism of estramustine phosphate and further studies are indicated to assess the clinical implications of these findings.
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PMID:Uptake, metabolism and antiproliferative effect of estramustine phosphate in human glioma cell lines. 269 86

A number of cytochrome P450s are targets for compounds that are clinically used or under clinical evaluation for treatment of patients with mycotic infections, such as dermatophytosis, superficial and systemic candidiasis, cryptococcosis and aspergillosis, with skin diseases, such as psoriasis or ichthyosis, and other retinoid-sensitive malignancies, e.g., neuro-ectodermal glioma. Some of the P450 inhibitors are candidates for the treatment of hirsutism or prostate cancer, others are potent inhibitors of the P450 isomerase involved in the synthesis of thromboxane A2, a potent platelet aggregation inducer and vasoconstrictor.
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PMID:P450 inhibitors of use in medical treatment: focus on mechanisms of action. 749 62

The human prostatic carcinoma cell line DU 145 was grown as multicellular spheroids in vitro. The volume doubling time during the early exponential growth phase was about 5 days. The saturation volume, in the plateau phase of the growth curve, was in the order of 1.4 mm3. The spheroids developed a central degenerative region surrounded by a 0.1-0.3 mm layer of viable cells. The DU 145 spheroid system is planned to be used as a model in studies on chemotherapy and targeted radiotherapy of micrometastases of prostatic cancer. Some effects of the drug estramustine, EM, a conjugate of estradiol and nornitrogen mustard, were analysed in this introductory study. Tritium-labelled estramustine, 3H-EM, bound both in the viable cell layers and in the degenerative region of the spheroid already after 1 hour of incubation which indicated good penetration. The viable cells bound only low levels of 3H-EM while the degenerative region bound 3H-EM to a higher extent. The amount of bound 3H-EM increased after incubation for 24 hours. The binding was nonspecific since it could not be inhibited by pretreatment with an excess of non-radioactive EM. Furthermore, 3H-EM bound to a similar extent in glioma and colon carcinoma spheroids used for comparison. Incubation of DU 145 spheroids for 24 hours with EM (20 mg/ml) induced a growth delay of 6-7 days and a transient increase in the volume of the extracellular spaces for a few days following the treatment. The results showed that the binding of EM to prostate DU 145 cells growing as spheroids was not specific and that the toxic action was limited. An interesting result was that EM works as an extracellular space expander. This might be exploited in combination treatments with other agents.
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PMID:Growth of prostatic cancer cells, DU 145, as multicellular spheroids and effects of estramustine. 823 95

Current treatment for disseminated prostate cancer, whether progressive or hormone-resistant, do not improve survival. Insulin growth factors (IGFs) are potent stimulants of prostate epithelial cells growth, their presence having been demonstrated in high quantities in several tumours such as lung, hepatoma, pheochromocytoma, malignant glioma and breast cancer. Local management of growth factors production could improve the results of second line therapy in hormone-resistant prostate cancer. Levels of IGF-I were determined by radioimmunoassay (RIA) in normal (n = 5), hyperplastic (n = 5) and tumoral (n = 8) prostate tissue. Presence of IGF-I is confirmed in all tissues (9.62 +/- 5.81; 8.32 +/- 7.81 and 6.02 +/- 1.42 ng/mg protein, respectively) but no significant differences are displayed among the three groups.
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PMID:[Insulin growth factor I (IGF-I) in normal, hyperplastic, and tumor prostatic tissue]. 876 97

Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.
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PMID:Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal. 991 26

The tumour suppressor gene PTEN/MMAC1, which is mutated or homozygously deleted in glioma, breast and prostate cancer, is mapped to a region of 10q which shows loss of heterozygosity (LOH) in bladder cancer. We screened 123 bladder tumours for LOH in the region of PTEN. In 53 informative muscle invasive tumours (> or = pT2), allele loss was detected in 13 (24.5%) and allelic imbalance in four tumours (overall frequency 32%). LOH was found in four of 60 (6.6%) informative, non-invasive tumours (pTa/pT1). We screened 63 muscle invasive tumours for PTEN mutations by single-strand conformation polymorphism (SSCP) analysis and for homozygous deletion by duplex quantitative polymerase chain reaction (PCR). Two homozygous deletions were identified but no mutations. Of 15 bladder tumour cell lines analysed, three showed homozygous deletion of all or part of the PTEN gene, but none had mutations detectable by SSCP analysis. Our results indicate that PTEN is involved in the development of some bladder tumours. The low frequency of mutation of the retained allele in tumours with 10q23 LOH suggests that there may be another predominant mechanism of inactivation of the second allele, for example small intragenic deletions, that hemizygosity may be sufficient for phenotypic effect, or that there is another target gene at 10q23.
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PMID:Somatic mutation of PTEN in bladder carcinoma. 1036 Jun 73


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