Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The environment of cells within solid tumors is known to be acidic relative to that in normal tissue, and the viability of tumor cells may depend on mechanisms which maintain intracellular pH (pHi) above the extracellular pH (pHe). We have assessed therefore the toxicity in vitro of the proton ionophore carbonylcyanide-3-chlorophenylhydrazone (CCCP), since this agent has been reported to be capable of transporting H+ equivalent through artificial lipid bilayers and mitochondrial membranes. CCCP was toxic to the human bladder carcinoma cell line MGHU1 and to the murine mammary sarcoma cell line EMT-6 only at pH, less than 6.5. CCCP transported H+ equivalents through cell membranes at physiological (7.35) and low pHc (6.20). Cell lines were found to have steady-state pHi values approximately 0.1 to 0.2 pH units above pHc at pHc less than 6.50. Addition of CCCP led to a decrease in steady-state pHi values as compared to untreated cells at pHc less than 6.50, whereas there was no apparent effect of CCCP on steady-state pHi values at pHc greater than 6.50. The CCCP-induced reduction in steady-state pHi combined with the uncoupling of oxidative phosphorylation by CCCP appeared to be the major mechanisms leading to cell death at pHc less than 6.50. The toxicity of CCCP under acidic conditions was enhanced by amiloride and 4,4'-diisothiocyanostilbene-2,2-disulfonic acid, agents which are known to inhibit membrane-based ion exchange mechanisms which regulate pHi under acidic conditions. When both agents were combined with CCCP, cell killing was observed at pHc less than 7.30. Our results suggest that mechanisms which regulate pHi under acidic conditions which occur in solid tumors may represent targets for new forms of tumor-specific therapy.
Cancer Res 1989 Aug 15
PMID:Reduction of intracellular pH as a possible mechanism for killing cells in acidic regions of solid tumors: effects of carbonylcyanide-3-chlorophenylhydrazone. 274 36

The gene for human adenosine deaminase (ADA), an enzyme constitutively expressed in all tissues investigated so far and deficient in some cases of severe combined immune deficiency, was previously assigned to chromosome 20 by syntenic analysis, using somatic cell hybrids and quantitative enzyme studies on patients with chromosome abnormalities. Attempts at regional localization of ADA through indirect approaches have so far resulted in uncertainties, as well as apparent inconsistencies. In situ hybridization of high-resolution somatic and pachytene chromosomes using a 3H-labeled cDNA probe of the ADA gene localized the gene to 20q12----q13.11. Rearrangements involving this region have been reported in various human hematological malignancies; in this regard, possible implications of the physical proximity of the ADA gene locus to that of SRC, an oncogene previously localized to the same region of chromosome 20, are briefly discussed.
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PMID:Localization of human adenosine deaminase (ADA) gene sequences to the q12----q13.11 region of chromosome 20 by in situ hybridization. 277 85

The Philadelphia (Ph) chromosome usually results from the t(9;22), which causes the physical association of the BCR1 and ABL genes and their function as a single new gene. This precise genomic mutation probably has a significant role in the development of leukemia in humans, but that leukemia may take several forms: chronic myeloid leukemia (CML), acute myeloid leukemia, acute lymphocytic leukemia, and essential thrombocythemia; CML also transforms to a lymphoid or myeloid acute phase. Two models are considered with regard to determinants of this variable hematologic expression of BCR-ABL. The first is variation in the breakpoint site of BCR1. Two breakpoint sites, M-BCR and m-BCR, are known, and their occurrence shows a nonrandom association with the different forms of leukemia. The precise position of the breakpoint within M-BCR may also be important. The second model concerns the role of other genes in determining the leukemic form shown by BCR-ABL. Results are reviewed of a patient who entered blast crisis CML and whose leukemic clones involved ten genetic loci with known leukemic associations. Many of these were probably genetic variants that allowed leukemic proliferations following the initiation of blast crisis. The multiplicity of these genes may obscure the prime determinant of blast crisis, which is unknown at the present time.
Cancer Genet Cytogenet 1989 Oct 01
PMID:The variable hematologic expression of the BCR-ABL genomic mutation and its possible determinants. 279 Jul 50

Effects of tumor, operative stress and tumor removal, and postoperative TPN of varying amino acid compositions on brain levels of tryptophan or tyrosine as predicted by their brain influx rates were studied in normals and in malnourished cancer patients. Concentrations of the large neutral amino acids (LNAA) were determined in patients before and after tumor removal, and in postoperative patients before and after receiving either a standard TPN solution (STD-TPN), or a branched-chain amino acid solution (BCAA-TPN). The LNAA were altered in all groups versus normals. Brain influx rates showed the following: in preoperative patients, predicted brain tryptophan levels were below normal (P less than 0.001), whereas tyrosine levels were within or above normal; no significant differences between pre- and postoperative tryptophan or tyrosine levels; postoperative STD-TPN did not change predicted brain tryptophan concentration from preinfusion values, but BCAA-TPN decreased it (P less than 0.001), underscoring the common transport carrier; and preinfusion predicted brain tyrosine levels were decreased (P less than 0.001) by both types of TPN solutions. These results imply low substrate levels for brain serotonin and catecholamine synthesis, possibly affecting functions dependent on their control.
Cancer 1987 Mar 15
PMID:Observations on predicted brain influx rates of neurotransmitter precursors. Effects of tumor, operative stress with tumor removal, and postoperative TPN of varying amino acid compositions. 288 Jun 57

The four main fractions of hematoporphyrin derivative were separated by high-pressure liquid chromatography. Each fraction was studied with respect to photosensitizing capabilities, fluorescence, and tumor tissue uptake in mice bearing EMT-6 tumors. Animals received i.p. injections of 10 mg/kg of each fraction, and 24 h later tumors either were treated with 100 J/cm2 of light (630 nm) to evaluate photosensitizing capabilities, or the animals were sacrificed and tumors removed for fluorescence and fraction uptake determination. The results indicate that the fraction responsible for photosensitization has the highest tumor tissue uptake and retention. Furthermore, this fraction demonstrates the highest overall fluorescence localization in neoplastic tissue. The other poorly photosensitizing fractions have a lower overall fluorescence in vivo due to their poor tumor tissue localization.
Cancer Res 1987 Feb 15
PMID:Biological studies on the main fractions of hematoporphyrin derivative. 294 36

Hyperthermia induced by a microwave source (2,450 MHz) was used alone and in combination with photodynamic therapy (PDT) to treat the SMT-F, EMT-6, and RIF animal tumors in vivo. PDT was administered using either Photofrin I or II as the photosensitizer and an argon-pumped tunable dye laser (630 nm) as the light source. Greater than additive increases in long-term tumor control were achieved when hyperthermia was given immediately post-PDT in the SMT-F and RIF tumor systems. Only additive (or independent) increases in tumor control were achieved when hyperthermia was given immediately before PDT in all these tumor systems and when heat was applied post-PDT using the EMT-6 tumor. In a series of experiments using the SMT-F tumor, it was observed that decreases in PDT drug or light doses could be offset (in terms of tumor control) by the addition of a subsequent heat treatment. This result, along with others presented, indicates the clinical potential of PDT and hyperthermia as adjuvant cancer modalities.
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PMID:Hyperthermic potentiation of photodynamic therapy employing Photofrin I and II: comparison of results using three animal tumor models. 295 50

The in vivo photosensitizing efficacy of mono-L-aspartyl chlorin has been studied by determining the percentage of BALB/c mice cured at varying doses of drug. Using an EMT-6 tumor model, animals received i.p. injections of mono-L-aspartyl chlorin (0.5-100 mg/kg) and then were subsequently exposed to light at 664 nm. Tumor biopsies were taken from selected animals sacrificed at 24 h after treatment and routine histopathological sections made. The other animals remained in the dark for a period of 6 weeks to determine the cure rate. Our results show that mono-L-aspartyl chlorin is an effective tumor localizer that brings about the selective degradation of tumor tissue following light exposure.
Cancer Res 1987 Sep 01
PMID:In vivo studies on the utilization of mono-L-aspartyl chlorin (NPe6) for photodynamic therapy. 295 47

The effect of photodynamic therapy on the tumor microvasculature in the first few hours after treatment was studied at the light and electron microscopy levels. BALB/c mice with EMT-6 tumor received ip injections of hematoporphyrin derivative, chlorin, or phthalocyanine, and 24 hours later, the tumors were treated with light at 100 J/cm2 at the appropriate therapeutic wavelength for each photosensitizer. Animals were killed and their tumors removed at time 0, 30 minutes, 1 hour, and 2, 4, 6, 8, 12, 16, and 24 hours after treatment. The results indicate that for all three sensitizers the effects of photodynamic therapy leading to rapid necrosis of tumor tissue are not the result of direct tumor cell kill but are secondary to destruction of the tumor microvasculature. The first observable signs of destruction occur in the subendothelial zone of the tumor capillary wall. This zone, composed of dense collagen fibers and other connective tissue elements, is destroyed in the first few hours after phototherapy. However, the ultrastructural changes seen in this zone are different for the hematoporphyrin derivative, compared with chlorin and phthalocyanine. Binding of photosensitizers to the elements in this zone as well as altered permeability and transport through the endothelial cell layer because of the increased intraluminal pressure may be key features of tumor destruction.
J Natl Cancer Inst 1988 Dec 21
PMID:Mechanism of tumor destruction following photodynamic therapy with hematoporphyrin derivative, chlorin, and phthalocyanine. 297 28

This laboratory has evaluated the subrenal capsular assay system previously in the Nb rat with the Nb rat prostate adenocarcinoma model. Human renal cell carcinoma xenografts are now being employed in our Nb rat SRC model, the advantage of this system being that one can determine the effect of chemotherapy in a very short period of time, i.e., 7 days. This method saves considerable time and expense and may serve as a useful indicator for effective chemotherapeutic agents in individual cancer patients. In our studies, cyclophosphamide was the only agent to produce a significant effect on tumor volume.
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PMID:First--generation human renal cell carcinoma xenografts in the Nb rat subrenal capsular assay model. 297 66

Human papillomaviruses (HPV) 16 and 18 are closely linked with human genital cancer. In most cervical carcinomas, viral sequences are integrated into the host genome. HeLa, a cervical carcinoma cell line, has multiple copies of integrated HPV 18 DNA. In this study, in situ chromosome hybridization was used to assign the integration sites of HPV 18 DNA sequences on HeLa cell chromosomes. Four sites of hybridization were identified at 8q23----q24, 9q31----q34, p11----p13 on an abnormal chromosome 5, and q12----q13 on an abnormal 22. Three of these sites correspond with the locations of MYC, ABL, and SIS protooncogenes, and are at or in close proximity to fragile sites. The chromosomal localization of HPV 18 DNA may be useful in assessing the role of viral integration in the development of this malignancy.
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PMID:Integration sites of human papillomavirus 18 DNA sequences on HeLa cell chromosomes. 302 16


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