Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.4.1 (phosphodiesterase)
 18,767 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It was shown on albino mice that when DOPA-3H (20 muCi/mouse) was administered before nonradioactive DOPA (1 mg/mouse) tritium accumulation in the tissue of Harding-Passi's melanoma of these mice proved to increase. Melanoma radioactivity in this experimental group was double that in the tumour tissue of the animals to which DOPA-3H alone was administered. Examination of the adenylate cyclase, phosphodiesterase activity and of the level of cAMP in melanoma of mice 2 hours after DOPA administration (1 mg/mouse) showed accumulation of cAMP and an increase in the phosphodiesterase activity; as to adenylate cyclase activity--it fell. It is suggested that DOPA realizes its effect not only as melanin precursor, but also through the cAMP system, influencing the melanogenesis enzymes activity.
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PMID:[Regulatory role of DOPA and components of the cyclic adenosine-3',5'-monophosphate system]. 20 73

Transfection of class I H-2Kb or H-2Kd into cells of a pigmented subclone of B16-F10 BL6 (termed BL6-8) results in the loss of melanin production. In contrast, transfected BL6-8 cells expressing H-2Dd, H-2Ld, class I H-21Ak and/or the neor genes maintained their pigmented phenotype. Melanogenesis was also inhibited in cells which expressed the endogenous H-2Kb, but not the endogenous H-2Db, gene. In order to identify the specific defects in the melanogenic pathway responsible for the absence of melanin production, factors known to be related to the regulation of pigment formation were evaluated in H-2K-expressing cells. These studies showed that: (1) transfection of BL6-8 cells with the H-2Kb or H-2Kd, but not with the H-2Dd, H-2Ld or H-21Ak, genes was associated with complete inhibition of tyrosinase activity; (2) alpha-melanocyte-stimulating hormone (MSH) and theophylline (an inhibitor of cAMP phosphodiesterase) failed to stimulate tyrosinase activity in H-2K-positive cells, whereas tyrosinase activities in untransfected, or H-2DdH-2Ld, neor or H-21Ak-transfected cells were dramatically increased by those agents; (3) treatment with MSH had no effect on cAMP levels in H-2K-positive cells but stimulated cAMP levels more than 100-fold in H-2K-negative cells; (4) in contrast to MSH, forskolin, a stimulator of adenylate cyclase, was able to stimulate cAMP levels in all cell lines tested, but in H-2Kb-positive cells the levels of forskolin-induced cAMP were significantly less than those elicited in H-2Kb-negative cells; (5) electron microscopy showed that H-2K-positive cells lacked mature melanosomes; (6) Northern blot analyses showed that H-2K-positive cells lacked mRNA for tyrosinase or for the MSH receptor. Taken together, expression of the endogenous or transfected H-2K gene in BL6 melanoma cells results in down-regulation of the entire melanogenic pathway, including the inhibition of tyrosinase and MSH receptor gene expression, cAMP responses and melanosomal biogenesis.
Melanoma Res 1995 Feb
PMID:Impairment of the melanogenic pathway in B16 melanoma cells transfected with class I H-2 genes. 773 52

Pentoxifylline (PX) is a phosphodiesterase inhibitor which effectively increases overall cAMP levels within the cell. This study analyses the ability of PX to alter growth, adhesion and lymphokine activated killer (LAK) cell-mediated lysis of the C8161 and Hs294T human melanoma cell lines, and investigates the role of intercellular adhesion molecule-1 (ICAM-1) in the tumour/LAK cell interaction. We have demonstrated that 4 days' pretreatment with PX (100-250 microg/ml) significantly reduces cell numbers in a dose- and time-dependent manner, with cell numbers decreasing by 67.5% in the C8161 cell line and by 65.4% in the Hs294T cell line with 250 microg/ml PX. Adherence of both cell lines to a range of extracellular matrix components is not affected by PX, with the exception of the C8161 cells, where 4 days' pretreatment with 250 microg/ml PX causes a 24.2% reduction in adherence to fibronectin. Four days' pretreatment of the tumour cells with 250 microg/ml PX leads to increased lysis of the C8161 cells and decreased lysis of the Hs294T cells. The addition of blocking ICAM-1 antibody (10 microg/ml) to the C8161 cells at an effector:tumour cell ratio of 40:1 causes a 2.3-fold reduction in lysis of both control and PX-treated cells. Addition of blocking ICAM-1 antibody (5 microg/ml) to Hs294T cells reduces lysis of control cells 1.8-fold. In PX-treated Hs294T cells, 10 microg/ml of blocking ICAM-1 antibody significantly reduces lysis 1.5-fold. The more aggressive C8161 cells produce 5-fold greater levels of soluble ICAM-1 (sICAM-1) than the poorly metastatic Hs294T cells. PX (10-250 microg/ml) causes a dose-dependent increase in sICAM-1 expression in both cell lines, with maximum increases of 4.7-fold and 4.3-fold in the Hs294T and C8161 cell lines, respectively, following 4 days' pretreatment with 250 microg/ml PX. Collectively, these data demonstrate the ability of PX to alter tumour cell growth, adhesion and LAK cell-mediated lysis and also support a role for the involvement of ICAM-1 in the tumour/LAK cell interaction.
Melanoma Res 1999 Feb
PMID:Pentoxifylline-induced modulation of melanoma cell growth, adhesion and lymphokine activated killer cell-mediated lysis. 1033 32

Melanoma is the most common malignant skin cancer, appears indestructible and is notoriously resistant to all current modalities of cancer treatment strategies. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, has shown to have radiosensitizing properties for a variety of cancers. Recently, we have shown that PTX exhibits antimetastatic and anti-angiogenic activities in B16F10 melanoma cells in vitro as well as in vivo. In the present study, we have demonstrated the anticancer and antimetastatic potential of PTX against A375 human melanoma cell line at sub-toxic doses. The results implicate that PTX at sub-toxic doses exhibited an inhibitory effect on the ability of cellular proliferation as shown by MTT and colony formation assay. It impedes migration and also induces apoptosis. A375 cells pretreated with PTX showed decrease in adhesion to both Matrigel and Collagen type IV. Further, Gelatin zymography result reveals that PTX treatment decreases the secretion of MMP2 and MMP9. Finally, PTX significantly inhibited A375 subcutaneous tumour xenograft growth without having any toxicity. Thus PTX at sub-toxic doses affected melanoma metastasis at multiple steps in vitro as well as tumour growth in vivo. These data demonstrate its antimetastatic potential and provide preclinical evidence for the development of PTX as a potential agent against metastatic melanoma.
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PMID:Preclinical evaluation of the antimetastatic efficacy of Pentoxifylline on A375 human melanoma cell line. 2308 70