Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Preliminary studies of RAS mutational activation in human testicular germ cell neoplasms have yielded conflicting results. Whereas two studies of clinical material revealed a significant incidence of N- and KRAS mutations, two studies of a variety of germ cell lines failed to document RAS mutations. To clarify the incidence of RAS mutations in these tumors, we studied archival paraffin-embedded, formalin-fixed orchiectomy specimens from 25 nonseminomas (NSGCT), 18 seminomas (SEM), and one Leydig cell tumor. For 14 of the 44 neoplasms, DNA was also available from nonmalignant testis adjacent to the tumor. Six age-matched patients had testes removed because of nonmalignant disease and were studied as controls. Polymerase chain reaction (PCR) amplified the K-, N-, and HRAS 12, 13, and 61 codons of these specimens, and mutations were detected with mutation-specific oligonucleotide probe hybridization of Southern and slot blots. Four mutations were found in KRAS 12 (4/44;[9.1%]). One seminoma [1/18(5.6%)] contained the mutation GGT(GLY)----CGT(ARG), and three NSGCT [3/25(12%)] were found to have GGT(GLY)----GAT(ASP) mutations. One of the NSGCT mutations was detected in adjacent nonmalignant tissue, but the corresponding tumor did not contain any detectable mutation. No mutations were detected at KRAS 13 or 61, in NRAS or HRAS 12, 13, or 61, or in the control normal testes. PCR, slot blots, and hybridizations were performed twice by two separate investigators for confirmation of results. PCR-generated mutation-specific positive controls were created for all possible RAS mutations, and these along with wild-type DNA controls were integral to interpretation of the oligonucleotide mismatch hybridization assay. By using positive and negative controls, we have detected a relatively low incidence of RAS mutations in archival human testicular germ cell tumors.
Genes Chromosomes Cancer 1992 Sep
PMID:Detection of RAS mutations in archival testicular germ cell tumors by polymerase chain reaction and oligonucleotide hybridization. 138 46

Malignancy is the result of multistep transformational changes of normal somatic cells. In the case of respiratory epithelial malignancies this process lasts for several years. Many methods have been explored to mimic this process in an extracorporal model. In the present investigation we combined several of these methods. Organ cultures were prepared from tracheal specimens and were then consecutively treated with human papilloma virus, benzo(a)pyrene, methylnitronitrosoguanine and tetradecanoyl phorbol acetate. Identical numbers of organ cultures from the same specimen were maintained without exposure to carcinogens. After 6 weeks these cultures were further cultivated either in mixed cultures (MC) with autologous isotopic fibroblasts or under the kidney capsule of the nude mouse (SRC). These two methods were combined after a few months: MC cells were transplanted under the SRC or SRC transplants were explanted in cell culture. This long-term selection procedure revealed striking differences between control and treated organ cultures. Three-dimensional structures containing epithelial cells were isolated from both organ cultures but survived more than 3 months only from treated cultures. Only MC from treated organ cultures produced nodules under SRC. The incidence and morphology of the nodules in the SRC were directly related to carcinogen treatment, with more nodules with pronounced epithelial cell atypia obtained from treated organ cultures. MC and SRC showed the importance of a time factor for selecting cells with changed growth behavior--increased time increased the incidence of such cells.
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PMID:Induction of transformation of human respiratory epithelium in vitro. Preliminary investigation. 141 47

Metallo naphthosulfobenzoporphyrazines sulfonated to different degrees (M-NSBP) were prepared, and their potential as photosensitizers for the photodynamic therapy (PDT) of cancer was evaluated. M-NSBP can be viewed as hybrid molecules between sulfophthalocyanines and naphthalocyanines resulting in distinct differences in the absorption spectra between the mono-through tetrasulfonated derivatives. This feature greatly facilited their purification. Using V-79 Chinese hamster cells in vitro, the disulfonated derivatives were found slightly more photoactive than the hydrophilic trisulfonated derivatives while the monosulfonated derivative was inactive, in spite of a sixfold higher cell uptake. In the case of the di- and trisulfonated derivatives, differences in phototoxicity correlated well with their relative cell uptake. Substitution of Al for Zn had little effect on the extent of phototoxicity of the M-NSBP. In vitro PDT of the EMT-6 cells after in vivo dye administration, revealed a similar potency for direct cell killing between the di- and trisulfonated AlOH-NSBP, while the monosulfonated analog was inactive. PDT with the amphiphilic disulfonated AlOH-NSBP on the EMT-6 mammary tumor in BALB/c mice induced a significant tumor response, while the monosulfonated derivative was much less active.
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PMID:Photodynamic properties of naphthosulfobenzoporphyrazines, novel asymmetric, amphiphilic phthalocyanine derivatives. 143 90

The Philadelphia (Ph1) chromosome, or its molecular counterpart, the BCR-ABL fusion gene, is a rare but important prognostic indicator in childhood acute lymphoblastic leukemia (ALL), but its impact on adult ALL has not been well ascertained. A prospective study of the BCR-ABL fusion gene was begun on patients entered on clinical trials conducted by the Cancer and Leukemia Group B (CALGB). All patients received intensive, multiagent chemotherapy that included daunorubicin. Over 2 years, 56 patients were studied for molecular evidence of a BCR-ABL gene using Southern blot and pulsed-field gel hybridization analysis. Results were compared with cytogenetic detection of a Ph1 chromosome, and clinical features were compared for the BCR-ABL-positive and -negative groups. Molecular methods detected the BCR-ABL gene in 30% of cases compared with cytogenetic detection of the Ph1 chromosome in only 23%. The majority of cases (76%) showed the p190 gene subtype similar to pediatric ALL; the BCR-ABL-positive cases displayed a more homogeneous immunophenotype than the BCR-ABL-negative cases and were predominantly CALLA positive (86%) and B-cell surface antigen positive (82%). The rate of achieving complete remission was similar in the BCR-ABL-positive and -negative groups (71% and 77%, respectively, P = .72). There were more early relapses in the BCR-ABL-positive group, resulting in a shorter remission duration that was especially marked in the CALLA-positive and B-cell antigen-positive populations. These preliminary data suggest that the impact of the BCR-ABL gene on clinical outcome in ALL may be on maintenance of complete remission (CR) rather than achievement of CR when aggressive, multiagent chemotherapy is used. This study identifies the BCR-ABL gene as an important factor in adult ALL and demonstrates the utility of molecular methods for its accurate diagnosis.
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PMID:Clinical significance of the BCR-ABL fusion gene in adult acute lymphoblastic leukemia: a Cancer and Leukemia Group B Study (8762). 146 14

Cell killing can be achieved in an acidic environment in tissue culture (medium pH less than 7.0) by agents (nigericin, carbonylcyanide-3-chlorophenylhydrazone (CCCP)) which transport protons from the extracellular space into the cytoplasm. Cell killing is enhanced when these agents are used in combination with compounds (amiloride, 4,4'-diisothiocyanostilbene-2,2'-disulfonic acid (DIDS)) which inhibit the membrane-based exchangers responsible for the regulation of intracellular pH (pHi). We describe experiments which assess the ability of these agents to kill tumour cells in spheroids and in vivo. Both nigericin and CCCP were observed to penetrate tissue based on their ability to kill tumour cells in spheroids. The mean extracellular pH (pHe) of the KHT fibrosarcoma and the EMT-6 sarcoma were observed to be 0.21 and 0.32 pH units more acidic than the mean pHe in muscle tissue. Intraperitoneal (i.p.) administration of the vasodilator hydralazine (10 mg kg-1) caused a reduction of the mean pHe of the KHT but not the EMT-6 tumour. Nigericin (2.5 mg kg-1, i.p.) plus amiloride (10 mg kg-1, i.p.) followed 30 min later by hydralazine (10 mg kg-1, i.p.) reduced the surviving fraction of cells in the KHT and EMT-6 tumours, but had minimal effects on growth delay. When KHT tumours were treated with 15 Gy X-rays followed immediately by nigericin plus amiloride and hydralazine a reduced surviving fraction as well as an increase in tumour growth delay was observed compared to radiation alone. The administration of nigericin (2.5 mg kg-1, i.p.) or the combination of nigericin (2.5 mg kg-1, i.p.) followed by hydralazine (10 mg kg-1, intravenous (i.v.)) resulted in reductions of tumour pHi of 0.27 and 0.29 pH units respectively as determined by 31P magnetic resonance spectroscopy (MRS). Our results show that the combination of nigericin and hydralazine (with or without amiloride) can kill cells in rodent solid tumours and that cell killing is associated with a reduction in the mean pHi of tumour cells.
Br J Cancer 1992 Aug
PMID:Effects of agents which inhibit the regulation of intracellular pH on murine solid tumours. 150 4

The prevalence of hairy leukoplakia was determined among 176 symptomatic HIV seropositive patients seen at the outpatient department of the Institute of Tropical Medicine in Antwerp, Belgium. Moreover, systematic tongue biopsies were performed during postmortem examination of 21 patients with AIDS, 100 HIV seronegative immunocompromised patients with haematologic or other malignancies and 100 HIV seronegative non-immunocompromised patients who died at the University Hospital Antwerp. Hairy leukoplakia was observed in 52 (29.5%) of the outpatients, but only in one (5%) of the AIDS patients in the postmortem study (P = 0.03). An explanation for this difference may be that significantly more AIDS patients who died had received either acyclovir or ganciclovir during the 3 months prior to the postmortem examination than the HIV seropositive outpatients during the 3 months prior to examination. Hairy leukoplakia occurred more often in Caucasian homosexual men with HIV infection (38%) than among heterosexual Africans with HIV infection (17%) (P = 0.06). Hairy leukoplakia was observed in none of the HIV seronegative patients.
Int J STD AIDS
PMID:The prevalence of hairy leukoplakia in HIV seropositive and HIV seronegative immunocompromised patients. 150 55

In the present study the potential of minocycline, a semisynthetic tetracycline that inhibits collagenase activity in vivo, as an adjuvant to standard anticancer therapies was explored in vitro and in vivo. In EMT-6 cells, minocycline proved to be only minimally cytotoxic, producing a 50% cell kill at concentrations of 132 and 220 microM in normally oxygenated and hypoxic cells, respectively, after 24 h exposure to the drug. In vitro, there appeared to be no interaction between minocycline and cisplatin (CDDP), melphalan, 4-hydroperoxycyclophosphamide, or radiation. In tumor-cell survival studies using the FSaIIC murine fibrosarcoma, short-term treatment with minocycline (5 x 5 mg/kg given over 24 h) was only minimally cytotoxic and did not alter the tumor response to a range of radiation doses. However, when minocycline (5 x 5 mg/kg given over 24 h) was added to treatment with cyclophosphamide, there was a 4-fold increase in FSaIIC tumor-cell killing across the dose range of cyclophosphamide doses tested, whereas the killing of bone marrow granulocyte macrophage colony-forming units (CFU-GM) remained unchanged. The Lewis lung carcinoma was used to assess the response of both the primary tumor and metastatic lung disease to treatment with minocycline (14 x 5 mg/kg) given alone or in combination with several cytotoxic anticancer drugs or with radiation delivered locally to the primary tumor. Of the various therapies tested, minocycline proved to be especially effective as an addition to treatment with cyclophosphamide both in increasing the response of the primary tumor and in reducing the number of lung metastases. The tumor growth delay produced by melphalan, radiation, Adriamycin, and bleomycin was also increased by the addition of minocycline to these therapies. These results indicate that minocycline given in clinically achievable doses may be an effective addition to some standard therapeutic regimens and that the mechanism of modulation by minocycline is likely to involve an effect of the drug on the host and not its direct interaction with other therapeutic modalities at the level of the tumor cell.
Cancer Chemother Pharmacol 1992
PMID:Minocycline in combination with chemotherapy or radiation therapy in vitro and in vivo. 150 76

The Philadelphia chromosome (Ph1) was the first genetic change to be associated consistently with leukemia, and it is one of the best understood on the molecular level. Because of this, it is an excellent model to investigate the application of molecular techniques to the clinical setting. These techniques are reviewed as are their clinical use in chronic myelogenous leukemia (CML), acute lymphoblastic leukemia (ALL), and transplantation. The Ph1 is caused by the fusion of two genes on chromosomes 9 and 22, resulting in the BCR-ABL fusion gene. This new gene is believed to be the cause of these Ph1-positive leukemias. The ability to detect the BCR-ABL fusion gene evolved from cytogenetic detection to Southern blot analysis, and now includes sophisticated techniques such as polymerase chain reaction (PCR) methods and pulsed-field gels. Diagnosis of the BCR-ABL fusion gene by Southern blot detection of bcr genetic rearrangements is the prototype of molecular cancer diagnosis. The sensitivity and clinical uses of this test are reviewed, especially its application to monitoring the response to treatment. PCR methods enable the researcher to detect 1 CML cell in a population of 10(5) cells. Clinical experience with PCR, especially in transplantation medicine, is providing a better understanding of the meaning of the terms "remission" and "cure." Newer techniques using fluorescent in situ hybridization have considerable potential for BCR-ABL detection, but no clinical experience has been gained with these techniques currently. The diagnosis of the BCR-ABL fusion gene in ALL has important clinical implications because it is the most common molecular genetic change in adult ALL and is associated with short remissions and poor outcome in all age groups. Diagnosis of the BCR-ABL fusion in ALL is difficult because the molecular findings are more heterogeneous than they are in CML. The methods available and their accuracy and sensitivity are compared. A review of their clinical impact is included.
Cancer 1992 Sep 15
PMID:The role of molecular techniques in the clinical management of leukemia. Lessons from the Philadelphia chromosome. 151 23

The cytotoxicities of D,L-tetraplatin and D-tetraplatin were evaluated at 37 degrees C, 42 degrees C and 43 degrees C at normal pH, at pH 6.45 and under normally oxygenated and hypoxic conditions in EMT-6 cells in vitro. The D-isomer was also tested in FSaIIC cells in vitro. Under these various conditions the pure D-isomer was very similar in cytotoxicity with the racemic mixture. Like cisplatin, both D,L- and D-tetraplatin were selectively cytotoxic toward normally oxygenated cells under acidic pH (6.45) conditions at 37 degrees C. In both cell lines the cytotoxicity of D,L- and D-tetraplatin was markedly increased at hyperthermic temperatures. Under the same conditions platinum levels in EMT-6 cells exposed to D,L- or D-tetraplatin were higher than in cells exposed to cisplatin, and unlike cisplatin there was an increase in intracellular platinum levels when the cells were exposed to D,L- or D-tetraplatin at 42 degrees C compared with 37 degrees C. The tumour growth delay of the FSaIIC fibrosarcoma was the same for D,L- and D-tetraplatin. A dose of 10 mg/kg intraperitoneally of tetraplatin produced a tumour growth delay of about 4.3 days which was increased to about 6 days with the addition of local hyperthermia (43 degrees C, 30 min) to the drug treatment. The tumour cell survival assay also showed no difference between D,L- and D-tetraplatin and a log-linear increase in tumour cell killing with increasing drug dose which was increased 1.5-3-fold with local hyperthermia. D,L- and D-tetraplatin were relatively much more cytotoxic toward bone marrow colony forming units of granulocyte-macrophage progenitors (CFU-GM) than was cisplatin and this cytotoxicity was increased about 5-10-fold under hyperthermic conditions. There was an increase in DNA crosslink formation in tumours when hyperthermia accompanied tetraplatin treatment. Overall, D,L- and D-tetraplatin produced very similar responses under hyperthermic conditions in both tumour and normal tissues, and may be a useful agent in combination with local hyperthermia.
Eur J Cancer 1992
PMID:Interaction of D,L- and D-tetraplatin with hyperthermia in vitro and in vivo. 152 97

Aluminium phthalocyanines substituted to different degrees with hydrophilic sulphonic acid and hydrophobic phthalimidomethyl groups were investigated in vivo as new agents for the photodynamic therapy of malignant tumours. Parameters studied included the photodynamic action on EMT-6 mammary tumours in BALB/c mice, the therapeutic window and the potential for direct cell killing, assayed via an in vivo/in vitro test. Although the efficiency of photoinactivation of the EMT-6 tumour increases by a factor of ten with reduction of the number of sulphonic acid groups from four to two, no further effect was seen with the addition of the hydrophobic phthalimidomethyl groups. Addition of the latter groups however increased the potential for direct cell killing by a factor of two and expanded the therapeutic window by a factor of four, thus improving the usefulness of the dye as a photosensitiser for the photodynamic therapy of cancer.
Br J Cancer 1992 Jun
PMID:Biological activities of phthalocyanines. XIV. Effect of hydrophobic phthalimidomethyl groups on the in vivo phototoxicity and mechanism of photodynamic action of sulphonated aluminium phthalocyanines. 161 52


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