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)

In a European joint project carried out in 6 laboratories a disease-oriented program was set up consisting of a panel of 7 tumor types, each represented by 4 to 8 different human tumor lines, for secondary screening of promising anticancer drugs. Human tumor lines were selected on the basis of differences in histology, growth rate, and sensitivity to conventional cytostatic agents. Xenografts were grown s.c. in nude mice, and treatment was started when tumors reached a mean diameter of 6 mm in groups of mice where at least 6 tumors were evaluable. Drugs were given at the maximum tolerated dose. For evaluation of drug efficacy, median tumor growth curves were drawn, and specific growth delay and treated/control x 100% were calculated. Doxorubicin (8 mg/kg i.v. days 1 and 8) was effective (treated/control < 50%, and specific growth delay > 1.0) in 0 of 2 breast cancers, 1 of 3 colorectal cancers, 2 of 5 head and neck cancers, 3 of 6 non-small cell lung cancers, 4 of 6 small cell lung cancers, 0 of 3 melanomas, and 3 of 6 ovarian cancer lines. Amsacrine (8 mg/kg i.v. days 1 and 8) was not effective, while datelliptium (35 mg/kg i.p. days 1 and 8) was active against 2 of 6 small cell lung cancer lines. Brequinar sodium (50 mg/kg i.p. days 1-5) showed efficacy in 4 of 5 head and neck cancers, 5 of 8 non-small cell lung cancers, and 4 of 5 small cell lung cancer lines. The project has been shown to be a feasible approach. Clinical activity for doxorubicin and inactivity for amsacrine against solid tumor types was confirmed in the human tumor xenograft panel. Additional anticancer drugs will be studied in the European joint project to further define the reliability of this novel, promising screening approach.
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PMID:Phase II preclinical drug screening in human tumor xenografts: a first European multicenter collaborative study. 139 20

The distribution of O6-methylguanine-DNA methyltransferase (MGMT) activity in extracts of tumors from 74 patients was measured. The results demonstrated that there was considerable variation of MGMT activity in different human tumor tissues as well as in different individuals. The mean values (X +/- SD, pmol/mg of protein) in breast cancer, stomach cancer, small cell lung cancer, non-small cell lung cancer, renal cell carcinoma, esophageal carcinoma, brain tumors, colon carcinoma and malignant melanoma were 1.071 +/- 0.374 (9), 0.515 +/- 0.107 (5), 0.509 +/- 0.251 (5), 0.461 +/- 0.227 (24), 0.329 +/- 0.246 (5), 0.273 +/- 0.376 (5), 0.244 +/- 0.175 (14), 0.242 +/- 0.308 (5) and 0.201 +/- 0.161 (2) respectively. It was notable that six samples (1/24 non-small cell lung cancer, 3/5 esophageal carcinoma, 1/14 brain tumors and 1/5 colon carcinoma) did not have any detectable level of MGMT activity. Activity of glutamine pyruvic transaminase (GPT) was also measured in the same extracts used for the assay of MGMT activity. The activity of GPT in these samples with undetectable level of MGMT activity was similar to those with significant MGMT activity. These results further strengthen the assumption that a certain fraction of human tumors are Mer-.
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PMID:O6-methylguanine-DNA methyltransferase activity in human tumors. 139 31

Etoposide and teniposide are closely related derivatives of podophyllotoxin, and both have a phase-specific action in the late S and early G2 phases of the cell cycle. Etoposide has attracted more widespread use and study, although no evidence suggests a differing mode of action or spectrum of anticancer activity. The drugs have significant differences in their clinical pharmacology, however. Teniposide exhibits greater protein-binding affinity, has a longer plasma terminal elimination half-life, and has reduced plasma and renal clearances. Little is accurately known about the metabolism of either drug, but the fact that 40% to 60% of administered etoposide is accounted for by excretion or metabolism, whereas the range is only 10% to 25% for teniposide, reflects a further difference between the drugs. Renal dysfunction impairs etoposide excretion, but the effect of hepatic impairment on drug clearance is unclear. A specific oral formulation exists only for etoposide, although the unpalatable intravenous preparations of both drugs can be taken orally. The bioavailability of oral etoposide is about 50% at doses of 200 mg or less and decreases as drug doses increase. There is considerable intrapatient and interpatient variation in etoposide absorption, but the reasons for this are unknown. In vitro, the efficacy of etoposide is highly dependent on the schedule of administration. The superior efficacy without increased toxicity of more prolonged schedules of etoposide administration has been demonstrated recently in patients with small cell lung cancer (SCLC). Although the optimal schedule in any specific tumor is not known, current pharmacodynamic evidence suggests that the efficacy of etoposide, at least in SCLC, is related to the maintenance of prolonged low blood concentrations of drug.
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PMID:Clinical pharmacology and schedule dependency of the podophyllotoxin derivatives. 141 35

Although teniposide activity in glioma was reported as early as 1971, it is only within the last 2 to 3 years that its effectiveness in small cell lung cancer and, most dramatically, in associated brain metastasis, has undergone long overdue systematic investigation. The drug appears to enjoy preferential uptake by brain-tumor tissue compared with disease-free brain tissue. Single-agent activity of teniposide in astrocytomas has been widely reported but the data are difficult to interpret due to differences among studies in definition of response and response duration. Combination therapy has focused primarily on teniposide with nitrosoureas and, again, definition variations have made it difficult to evaluate data. Similar problems plague trials by one group of investigators who reported that the combination of teniposide with doxorubicin and lomustine resulted in regression or improvement in significant percentages of their patients. While many studies indicate that teniposide has significant potential in treatment of adult glioma, controlled trials are needed to evaluate and optimize the use of this agent.
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PMID:Teniposide (VM-26) in brain tumors. 141 42

The N-myc oncogene has been implicated in the pathogenesis of a number of human tumors, including childhood neuroblastoma and adult small cell lung cancer. We have isolated and characterized complementary DNA clones derived from a transcription unit, N-cym, located on the opposite DNA strand to N-myc, with extensive overlap existing between the 5' ends of the two transcription units. The N-cym gene, which can encode a 109-amino acid protein, is expressed during fetal development, as well as in tumor cell lines containing amplified N-myc loci, where it is expressed at very high levels. Although other examples of overlapping, opposite-strand eukaryotic genes exist, N-myc and N-cym are unique in that they appear to be coregulated in tumor cell lines under basal growth conditions and in response to the differentiating agent retinoic acid. This coregulation suggests that their protein products may be functionally interrelated during normal development and oncogenesis.
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PMID:Isolation and characterization of complementary DNA for N-cym, a gene encoded by the DNA strand opposite to N-myc. 141 2

The cytotoxic activity of cyclosporin A (CsA) and the three non-immuno-suppressive CsA analogues B3-243, WO-039 and B3-665 were studied in tumor cell lines representing both classical and atypical forms of multidrug resistance (MDR): T-ALL GM3639 L100 cells selected for vincristine (vcr) resistance and displaying characteristics of classical MDR, including P-glycoprotein (pgp) expression and increased drug efflux which can be inhibited by pgp blockers (e.g. verapamil), and U-1285/ADR, a small cell lung cancer (SCLC) cell line selected for doxorubicin resistance which lacks pgp, is insensitive to pgp-blockers and shows cross resistance to cis-platinum. At 1 micrograms/ml CsA was the most active agent in reversing Vcr resistance in L100 cells followed by B3-243 and WO-039, with no effect of B3-665. Parental LO cells were only marginally sensitized to Vcr by these agents. No reversing effect of any cyclosporin was observed in the U-1285/ADR or its parental cell line. Compared to LO cells, L100 cells showed a marked hypersensitivity to CsA > B3-243 > WO-039 with B3-665 being inactive. No collateral sensitivity was observed for cyclosporins in U-1285/ADR cells. Although of different magnitude, the pattern of cytotoxic activity for the different cyclosporins alone closely parallelled that of L100 cells for U-1285, U1285/ADR and LO cells. The results indicate that not only the collateral sensitivity in classical MDR but also the cytotoxic actions of cyclosporins per se on tumor cells alone are independent of immunosuppressive activity. The results also suggest a structure-activity relationship for cyclosporin-induced cytotoxicity similar to, but independent of, MDR reversing activity.
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PMID:Cytotoxic action of cyclosporins on human tumor cell lines is not dependent on immunosuppressive activity. 144 25

Etoposide is an important antineoplastic drug. Despite the use of several combination chemotherapy regimens that include etoposide, the best dose and schedule for etoposide remains unknown. The schedule dependency for small cell lung cancer is now known, and it is likely the same for other sensitive neoplasms (ie, lymphoma, germ cell tumors). Recent data suggest that even a more extended schedule of administration (ie, 14 to 21 days) may be more effective than the standard 3- to 5-day schedule. Several studies have assessed plasma levels in reference to dose, schedule, and tumor responsiveness. Preliminary data suggest that high peak levels (ie, > 5 to 10 micrograms/mL) are associated with more severe myelosuppression than lower peak plasma levels (ie, 1 to 3 micrograms/mL). Response rates and survival in small cell lung cancer patients given low daily doses for 14 to 21 days are comparable with results achieved with standard doses given for 3 to 5 days. Preliminary data from several studies suggest that administering low doses for a prolonged schedule is a superior method of etoposide administration. Other studies including randomized comparisons are necessary to confirm these observations.
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PMID:Etoposide: seeking the best dose and schedule. 148 56

A panel of 60 human tumor cell lines is currently being used in the U.S. National Cancer Institute's in vitro anticancer drug screen. The panel is organized into 7 subpanels; 6 leukemia/lymphoma lines comprise one subpanel, and 54 other lines are organized into subpanels representing solid tumors of the central nervous system (CNS), colon, lung, ovaries, kidneys and melanomas. In the present study, the leukemia and lymphoma cell lines were analyzed by flow cytometry for appropriate CD antigens; all but 1 line showed patterns of expression consistent with their reported derivations. The solid tumor lines were characterized individually using morphological and immunocytochemical techniques to determine their relative degrees of representativity for the subpanels within which they are currently grouped. Histological, histochemical and ultrastructural examinations were performed on cell lines grown under identical conventional culture conditions and as xenografts in nude mice. Immunocytochemistry using panels of antibodies raised against 6 types of intermediate filaments, 7 adenocarcinoma-associated antigens, 7 melanoma/neuro-ectodermal-associated antigens, 3 neuroendocrine-associated antigens, 9 urinary tract associated antigens, and 4 markers of muscle differentiation was done on cells grown in monolayer culture. Central nervous system (CNS) cell lines lacked expression of glial fibrillary acidic protein, but all had other features consistent with derivation from glioblastoma. Lines derived from adenocarcinomas of the colon, lung and ovary, for the most part, expressed adenocarcinoma-associated antigens and showed histological and/or ultrastructural evidence of gland formation and other adenomatous features. Most of these lines were poorly differentiated. Lines derived from large-cell and squamous-cell cancers also showed some characteristics consistent with their reported origins, except for one line which showed immunocytochemical and morphologic characteristics consistent with rhabdomyosarcoma. The 2 lines derived from small cell lung cancer (SCLC) lacked neurosecretory granules and 3 other SCLC markers but showed morphologic features consistent with SCLC. Most melanoma cell lines strongly expressed melanoma-associated antigens and were morphologically similar to human melanoma. Five lines produced premelanosomes, melanosomes or melanin. Most of the renal cancer cell lines showed morphologic or immunocytochemical features consistent with renal clear cell carcinoma. Collectively, these morphological and immunocytochemical analyses provide information concerning tissue of origin, tumor type, degree of differentiation and other biologic features essential to the use of these lines in a disease-oriented in vitro antitumor drug screen and to the interpretation of data derived therefrom.
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PMID:Morphological and immunocytochemical characteristics of human tumor cell lines for use in a disease-oriented anticancer drug screen. 150 99

Recent progress in elucidating the complex and heterogeneous interactions between malignancy and coagulation or fibrinolysis reactions in humans has clarified the pathogenesis of disseminated intravascular coagulation that occurs with malignancy and has revealed evidence for two distinct pathways of growth regulation based on production by tumor cells of initiators of thrombin formation versus plasminogen activators. We have proposed a preliminary classification of tumors (see Table 2) based on these interactions. Type I tumors are those in which the tumor cells are associated with an intact coagulation pathway that leads to thrombin formation at the tumor periphery but in which the tumor cells lack u-PA. Examples of tumors in this category include SCCL, malignant melanoma, and renal cell carcinoma. Type II tumors are those in which the tumor cells express u-PA but lack an associated coagulation pathway leading to thrombin formation. Examples of type II tumors include prostate cancer, colon cancer, breast cancer, and N-SCLC. Type III tumors are those that express neither of these pathways, or exhibit some other pattern of interaction. Obviously, this formulation must be regarded as hypothetical. However, this concept fits with the limited data available to date from clinical trials. More importantly, this hypothesis can be tested further by means of intervention aimed at interrupting pathways relevant to specific tumor types. Characterization of additional tumor types by the methods described should permit amplification of this classification of tumors and other patterns of interaction may be defined. Exploration of the coagulation-cancer interaction holds considerable promise for gaining new understanding of both the coagulation mechanism and tumor biology. Most intriguing is the prospect that imaginative approaches to cancer treatment may be devised that are not only relatively nontoxic and low cost, but also effective.
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PMID:Pathways of coagulation/fibrinolysis activation in malignancy. 157 11

Paraneoplastic syndromes are caused by factors produced by cancer cells that often act at a site distant from both the primary site and its metastases. These syndromes are estimated to occur in only 7% to 15% of patients with cancer and are diagnoses of exclusion. If the definition of paraneoplastic syndrome is broadened to include indirect effects of the tumor such as cachexia or the anemia of chronic disease, the incidence is much higher. Lung cancer, particularly small cell lung cancer, is the most common malignancy causing paraneoplastic syndromes. This review focuses on recently published literature on paraneoplastic syndromes associated with lung cancer, including humoral hypercalcemia of malignancy, autoimmune paraneoplastic neurologic syndromes, neuromuscular disorders, and cancer cachexia. It includes advances in both molecular biology and immunology, and in clinical investigation.
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PMID:Paraneoplastic syndromes in lung cancer. 159 5


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