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Of all the different types of metastatic malignant tumors of the oral and maxillofacial region, metastasis to the tongue from the esophagus is rare. Here, we report a case of esophageal cancer that metastasized to the tongue. A 59-year-old man who had been diagnosed with esophageal cancer and was undergoing postoperative chemotherapy was referred to our department with a mass and pain on contact in the left side of the tongue one month previously. An elastic hard mass with a normal surface mucosa was found on the left side of the tongue. Histopathological analysis of a biopsy specimen taken from the lesion confirmed that it was a squamous cell carcinoma; no continuity was observed between the tumor and the mucosal epithelium, and the tumor was histopathologically similar to esophageal cancer. Resection of the tongue was performed because the eating disorder had a profound effect on the patient’s daily life. He was ultimately diagnosed as having a tongue metastasis from an esophageal primary cancer. Subsequently, mediastinal lymph node swelling was observed, and chemotherapy as well as radiation therapy were performed at the referring hospital, but he died one year after tongue resection. There was no recurrence of the tongue tumor, and oral ingestion and outpatient visits were possible up to two weeks prior to the patient’s death.

Background/aim The prognosis of patients with osteosarcoma is poor; therefore, new treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of the 11 families (PDE1-PDE11) of the phosphodiesterase superfamily that regulates the intracellular concentrations and effects of cAMP and cGMP. This in vitro study was performed to investigate the role of PDE2 in human oral osteosarcoma HOSM-1 cells. Materials and methods PDE2 expression was measured by a cAMP-PDE assay and real-time-PCR. The effects of the PDE2-specific inhibitors, erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), 8-bromo-cAMP, and 8-bromo-cGMP on cell proliferation and migration were assessed. Results PDE2 activity and PDE2A mRNA expression were detected in HOSM-1 cells. Cell proliferation was inhibited by EHNA and 8-bromo-cAMP but not by 8-bromo-cGMP. Cell migration was stimulated by EHNA and 8-bromo-cGMP, but it was inhibited by 8-bromo-cAMP. Conclusion Cell proliferation is regulated by PDE2-cAMP signaling and cell migration is regulated by PDE2-cGMP signaling in HOSM-1 cells.

Background/aim Due to its abilities of substance adsorption and intracellular transportation, hydroxyapatite is a potential carrier in drug delivery systems (DDS). This in vitro study investigated whether newly-developed, highly-dispersive calcined hydroxyapatite nanoparticles with an average grain diameter of 20 nm (nano-SHAP) were suitable as a DDS for the drugs zoledronic acid (ZA), cisplatin, and carboplatin. Material and methods The effects of drug-bearing nano-SHAP on cell proliferation were assessed using three human oral squamous cell carcinoma cell lines (HSC-4, KOSC, and SAS) and one human breast cancer cell line (MCF-7). Results Nano-SHAP alone did not affect proliferation of any cell line until a concentration of 1 μg/ml was reached. Although the effective concentration of ZA in ZA-bearing nano-SHAP differed, it inhibited cell proliferation better than ZA alone. Cisplatin and carboplatin-bearing nano-SHAP had the same effect as these drugs alone. Conclusion The nano-SHAP system is of potential use as a drug delivery system.

Chédiak–Higashi syndrome (CHS), a rare autosomal recessive disorder associated with leukocyte dysfunction, is characterised by partial skin and hair albinism, immunodeficiency, and abnormal bleeding. Furthermore, it may be associated with cognitive and neurological impairments. The long-term prognosis of patients is generally poor, and haematopoietic stem cell transplantation is a radical immunodeficiency treatment. Here, we report a case of successful oral management of an 18-year-old woman with CHS accompanied by aggressive periodontitis who underwent haematopoietic stem cell transplantation.

Cyclic nucleotide phosphodiesterases (PDEs) regulate the intracellular concentrations and effects of adenosine 3′,5′-cyclic monophosphate (cAMP) and guanosine 3′,5′-cyclic monophosphate (cGMP). The role of PDEs in malignant tumor cells is still uncertain. The role of PDEs, especially PDE2, in human malignant melanoma PMP cell line was examined in this study. In PMP cells, 8-bromo-cAMP, a cAMP analog, inhibited cell growth and invasion. However, 8-bromo-cGMP, a cGMP analog, had little or no effect. PDE2 and PDE4, but not PDE3, were expressed in PMP cells. Growth and invasion of PMP cells were inhibited by erythro-9-(2-hydroxy-3-nonyl) adenine (EHNA), a specific PDE2 inhibitor, but not by rolipram, a specific PDE4 inhibitor. Moreover, cell growth and invasion were inhibited by transfection of small interfering RNAs (siRNAs) specific for PDE2A and a catalytically-dead mutant of PDE2A. After treating cells with EHNA or rolipram, intracellular cAMP concentrations were increased. Growth and invasion were stimulated by PKA14-22, a PKA inhibitor, and inhibited by N6-benzoyl-c AMP, a PKA specific cAMP analog, whereas 8-(4-chlorophenylthio)-2′-O-methyl-cAMP, an Epac specific cAMP analog, did not. Invasion, but not growth, was stimulated by A-kinase anchor protein (AKAP) St-Ht31 inhibitory peptide. Based on these results, PDE2 appears to play an important role in growth and invasion of the human malignant melanoma PMP cell line. Selectively suppressing PDE2 might possibly inhibit growth and invasion of other malignant tumor cell lines.

Odontogenic fibroma is a relatively rare and benign odontogenic tumor of mesodermal dental sac or periodontal ligament origin. We report a case of central odontogenic fibroma (COF) mimicking a dentigerous cyst associated with an impacted left mandibular third molar, together with immunohistological studies and a literature review. Including present case, a total of 24 cases of COF have been investigated immunohistologically to determine the origin of epithelial components or fibroblasts found in the parenchyma of the tumors. In the present case, the epithelial components were strongly positive for cytokeratin (CK AE1/AE3), and the fibroblasts were positive for vimentin. The site around the hard tissue was strongly stained by vimentin. Surgical findings indicated that the tumor extended to the periodontal ligament, suggesting that the tumor possibly originated in the periodontal ligament. A review of the literature revealed that COF occurs in the fourth to fifth decade, exhibits no sex difference, and has a good prognosis after surgery. Radiographic images of COF occasionally mimic dentigerous cysts, but there are no particular radiographic features distinguishing COF. Diagnosis is usually based on histological findings. Immunohistological studies may also be useful in the diagnosis of COF.

Bullous pemphigoid is an autoimmune bullous disease occurring primarily in the skin, and initial onset in the oral mucosa is quite rare. A case of bullous pemphigoid with initial onset in the gingiva is reported. The patient was a 42-year-old female who presented with a primary complaint of recurrent gingival bullae that had appeared 9 months earlier. Enzyme-linked immunosorbent assay (ELISA) analysis of the patient's serum showed a positive reaction for anti-bullous pemphigoid 180 kDa antibodies (anti-BP180-NC16a antibodies). Immunohistochemical staining of a biopsy sample also revealed deposition of IgG and complement C3 in the basement membrane. With the use of an azulene gargle and topical application of a steroid ointment, the condition remained stable, but six weeks later, bullae also appeared around the navel, on the back, and on one lower leg. Use of a topical steroid ointment prescribed by a dermatologist was ineffective, so that, after one month, the patient was treated with oral administration of minocycline, and the symptoms in the mouth and skin improved. In this case, bullous pemphigoid with initial gingival onset was diagnosed at an early stage by ELISA analysis, and a satisfactory outcome was obtained without systemic use of steroid, which has commonly been used in the past.

Cetuximab is remarkable for the relatively high rate and severity of hypersensitivity reactions (HR) being reported in the literature. Screening for cetuximab‐specific IgE in serum via immunoassay has been found to be useful in preventing HR; however, these tests are known to have a low positive predictive rate. In an attempt to remedy this, we evaluated the interaction between cetuximab and IgE on basophils for predicting severe cetuximab‐induced HR. Twelve head and neck cancer patients were enrolled in this single‐institution study: four with a history of cetuximab‐induced HR and eight with no such history. Cetuximab‐specific and galactose‐α‐1,3‐galactose (α‐gal) specific IgEs in serum were measured in vitro using an enzyme‐linked immunosorbent assay (ELISA). IgE‐cetuximab binding on basophils was also analyzed to evaluate the decrease in cetuximab molecules on basophils after dissociation of IgE from FcεRI. The positive predictive value associated with the presence of cetuximab‐ or α‐gal‐specific IgE in serum was found to be only 0.67, whereas the negative predictive value was 1.00. On the other hand, in all four patients who developed HR, the cetuximab molecules on basophils were decreased significantly due to the dissociation of IgE from basophils (P

Xeroderma pigmentosum is a rare, autosomal recessive genetic disease accompanied by abnormal DNA function due to damage by ultraviolet radiation. Xeroderma pigmentosum typically has general features of high light sensitivity and a high incidence of skin cancer in regions exposed to sunlight. We report the case of squamous cell carcinoma of the lower lip in an 82-year-old patient with xeroderma pigmentosum who was successfully treated with peplomycin after first receiving treatment for diabetes.

Objective: To evaluate the effects of various 3-hydroxy-3-methylglutaryl-coenzyme A reductase inhibitors (statins) on ectopic osteoinduction by recombinant human bone morphogenetic protein-2 (rhBMP-2) using different administration methods. Materials and methods: Disks containing 5 μg of rhBMP-2 and type I collagen were implanted into the calf muscles of 6-week-old male rats (n = 64). Either the lactone form of simvastatin (SV), open hydroxy-acid form of simvastatin (SVA), cerivastatin (CVA), or vehicle (control) was then administered per orally (PO group) or subcutaneously (SC group) for 20 days. The disks were removed on day 21 after implantation, and ectopic induced bone formation was evaluated by radiographic, histologic, and biochemical analysis. Results: Both the projected and radiopaque area on X-ray film, and the calcium content of the SV group in the SC group (SV–SC group) were significantly greater than those in the other SC and PO groups. Alkaline phosphatase activity and tartrate-resistant acid phosphatase activity in the SV–SC group were significantly lower than those in the other SC and PO groups. Histologic examination revealed an increase of ectopic induced bone volume in the SV–SC group. Conclusion: Subcutaneous administration of SV stimulates ectopic osteoinduction by rhBMP-2 through reduction of bone turnover.

Phosphodiesterase (PDE) 3 has been characterized in isolated rat submandibular acini. PDE3 activity was detected in homogenates of isolated rat submandibular acini; little or no PDE3 activity was found in ducts. About 62% of PDE3 activity in the acini was recovered in the supernatant fractions; 38% in particulate fractions. In the acini, but not ducts, PDE3A mRNA was detected by reverse transcriptase-polymerase chain reaction (RT-PCR). The PDE3-specific inhibitor, cilostamide, increased the ratio of apomucin mRNA/18s rRNA, as quantified by real-time RT-PCR. Our results indicate that PDE3A may be important in regulating cAMP pools that control acini functions.

Objective: To investigate the characteristics of ectopic chondroid/bone matrix and chondrogenic/osteogenic cells induced by recombinant human bone morphogenetic protein-2 (rhBMP-2). Materials and methods: rhBMP-2 (5 μg) combined with atelocollagen was implanted into calf muscles of rats and removed on days 7, 10, 14, 21, or 28. Tissue sections were examined using: (i) hematoxylin/Alcian blue/Sirius red stain, (ii) enzyme histochemistry for alkaline phosphatase (ALP) and tartrate-resistant acid phosphatase activity, (iii) immunohistochemistry for types I, II, and X collagen, and (iv) electron microscopy. Results: On day 7, numerous fibroblast-like cells with ALP activity were present on the pellet rim. On day 10, chondroid matrix (CM) had formed, contained both type I collagen and proteoglycans, and often continued into the BMP pellet. On day 14, bone-like matrix formed around hypertrophic chondrocytes simultaneously with endochondral ossification. Coexpression of types I and II collagen within chondrocytes and osteocytes was observed throughout the time course of the experiment. Conclusion: These results suggest that fibroblast-like cells invading the pellet differentiate into chondrocytes and form CM under the scaffold of the carrier component. It appears that some chondrocytes change their phenotype to produce the bone-like matrix and remain within the endochondral bone. This process enables rapid osteogenesis to occur.

Reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that HOSM-1 cells, an osteosarcoma cell line established from human mandible, expressed mRNA for osteoblastic markers, such as alkaline phosphatase, osteonectin, osteocalcin and parathyroid hormone receptor, thus exhibiting an osteoblastic phenotype. We have investigated a possible role of cyclic nucleotide phosphodiesterases (PDEs) in osteosarcoma cells. RT-PCR analysis revealed that HOSM-1 cells expressed mRNA for PDE4A, 4B and 4C. In addition, rolipram, a specific inhibitor of PDE4, inhibited HOSM-1 cell proliferation. The finding that PDE4 is involved in proliferation of osteosarcoma cells suggests the possibility that PDE4 may be a new target for antitumor therapy.

This is a report of a 45-year-old woman in whom ameloblastoma recurred in the soft tissues 14 years after resection of the mandible. From the age of 14 years she had received conservative treatmentfor the recurrence of multiple intraosseous tumours.

Phosphodiesterase (PDE) 3s have been characterized in human squamous cell carcinoma KB cells. PDE3 activity was detected in homogenates of KB cells. PDE3A and 3B mRNAs were detected by RT-PCR in RNA from KB cells; the nucleotide sequences of the fragments were identical to those of human PDE3A and 3B. Immunoblotting with anti-PDE3 antibodies detected both PDE3A- and 3B-immunoreactive proteins in KB cells. The PDE3-specific inhibitor, cilostamide, inhibited the proliferation of KB cells. Our results indicate that PDE3s may be important regulators of the growth of KB cells. Therefore, PDE3 inhibitors may be potential new drugs for antiproliferative therapies in squamous cell carcinoma in the head and neck.

A recent preliminary (unpublished) study showed that phosphodiesterase (PDE) 3A and 3B are expressed in rat submandibular glands. Here, PDE3 activity was detected in homogenates of rat submandibular gland acinar epithelial (SMIE) cells, but not rat A5 (epithelial duct) cells. Most of the PDE3 activity in SMIE cells was recovered in the particulate fraction. Only PDE3B mRNA was detected by reverse transcription-polymerase chain reaction in RNA from SMIE cells. The nucleotide sequence of the fragment was identical to the sequence of rat PDE3B. The PDE3 specific inhibitor, OPC3689 (10 and 50 microM), inhibited the growth of SMIE cells (19 and 63%), but not A5 cells. As the submandibular gland contains many types of cells, these results indicate that PDE3B may regulate a cAMP pool that is important in submandibular gland acinar epithelial cell function.

Ameloblastomas frequently occur in relatively young people, but are rarely seen in people aged 80 years or older. We report a case of mandibular ameloblastoma in an elderly patient with a review of the literature. The patient was a 82-year-old man who noticed swelling of the gingiva approximately 2 weeks prior to his initial visit. Computed tomography showed a radiolucent area with little radiopacity. Internal uniformity was observed at the site, with thinning of cortical bone which lacked continuity in some areas. The excision and curettage were performed under general anaesthesia. No recurrence has been observed 14 months after surgery.

The prognosis for malignant melanoma is poor; therefore, new diagnostic methods and treatment strategies are urgently needed. Phosphodiesterase 2 (PDE2) is one of 21 phosphodiesterases, which are divided into 11 families (PDE1-PDE11). PDE2 hydrolyzes cyclic AMP (cAMP) and cyclic GMP (cGMP), and its binding to cGMP enhances the hydrolysis of cAMP. We previously reported the expression of PDE1, PDE3 and PDE5 in human malignant melanoma cells. However, the expression of PDE2 in these cells has not been investigated. Herein, we examined the expression of PDE2A and its role in human oral malignant melanoma PMP cells. Sequencing of RT-PCR products revealed that PDE2A2 was the only variant expressed in PMP cells. Four point mutations were detected; one missense mutation at nucleotide position 734 (from C to T) resulted in the substitution of threonine with isoleucine at amino acid position 214. The other three were silent mutations. An in vitro migration assay and a terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling assay revealed that suppressing PDE2 activity with its specific inhibitor, erythro-9-(2-hydroxy-3-nonyl)-adenine (EHNA), had no impact on cell motility or apoptosis. Furthermore, the cytotoxicity of EHNA, assessed using a trypan blue exclusion assay, was negligible. On the other hand, assessment of cell proliferation by BrdU incorporation and cell cycle analysis by flow cytometry revealed that EHNA treatment inhibited DNA synthesis and increased the percentage of G2/M-arrested cells. Furthermore, cyclin A mRNA expression was downregulated, while cyclin E mRNA expression was upregulated in EHNA-treated cells. Our results demonstrated that the PDE2A2 variant carrying point mutations is expressed in PMP cells and may affect cell cycle progression by modulating cyclin A expression. Thus, PDE2A2 is a possible new molecular target for the treatment of malignant melanoma.

Phosphodiesterases (PDEs) are important regulators of signal transduction processes. Eleven PDE gene families (PDE1-11) have been identified and several PDE isoforms are selectively expressed in various cell types. PDE4 family members specifically hydrolyze cyclic AMP (cAMP). Four genes (PDE4A-D) are known to encode PDE4 enzymes, with additional diversity generated by the use of alternative mRNA splicing and the use of different promoters. While PDE4 selective inhibitors show therapeutic potential for treating major diseases such as asthma and chronic obstructive pulmonary disease, little is known concerning the role of PDE4 in malignant melanoma. In this study, we examined the role of PDE4 in mouse B16-F10 melanoma cells. In these cells, PDE4 activity was found to be ∼60% of total PDE activity. RT-PCR detected only PDE4B and PDE4D mRNA. Cell growth was inhibited by the cAMP analog, 8-bromo-cAMP, but not by the specific PDE4 inhibitors, rolipram and denbufylline, which increased intracellular cAMP concentrations. Finally, migration of the B16-F10 cells was inhibited by the PDE4 inhibitors and 8-bromo-cAMP, while migration was increased by a protein kinase A (PKA) inhibitor, PKI(14-22), and was not affected by 8-pCPT-2'-O-Me-cAMP, which is an analog of exchange protein activated by cAMP (Epac). The inhibitory effect of rolipram on migration was reversed by PKI(14-22). Based on these results, PDE4 appears to play an important role in the migration of B16-F10 cells, and therefore may be a novel target for the treatment of malignant melanoma.

Eleven phosphodiesterase (PDE) gene families (PDE1-11) have been identified, and some PDE isoforms are selectively expressed in various cell types. Previously, we reported PDE1, PDE3 and PDE4 expressions in human malignant melanoma cells. However, the expression and role of PDE5 in malignant melanoma cells is not clear. Therefore, we characterized PDE5 in human malignant melanoma MAA cells.PDE5 activity and PDE5A mRNA expression were investigated in MAA cells. The full open reading frames for human PDE5A1 were sequenced. Effects of PDE5 inhibitors on cell growth were determined by 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt (MTS) assays.PDE5 activity and PDE5A1 mRNA expression were detected in MAA cells. The nucleotide sequence of PDE5A1 was identical to that of human PDE5A1, previously published. Two PDE5 inhibitors inhibited the growth of cells.PDE5A1 mRNA is expressed and may play an important role in the growth of human malignant melanoma MAA cells.

Cyclic adenosine 3'5'-monophosphate (cAMP) and cyclic guanosine 3'5'-monophosphate (cGMP) are critical intracellular messengers involved in transduction of signals generated by a wide variety of extracellular stimuli, including growth factors, cytokines, peptide hormones, light and neurotransmitters. These messengers modulate many fundamental biological processes, including myocardial contractility, platelet aggregation, vascular smooth muscle relaxation, proliferation and apoptosis, etc. Cyclic nucleotide phosphodiesterases (PDEs) catalyze the hydrolysis of cAMP and cGMP, and are important in regulating intracellular concentrations and biological actions of these signal-transducing molecules. These enzymes contain at least 11 highly regulated and structurally related gene families (PDE1-11). In this review, we will discuss some general information of PDEs and then focus on PDE3 gene family, including the molecular biology, structure, function and potential as therapeutic targets. Furthermore, we show the possibilities of PDE3 as therapeutic targets in malignant tumor cells and salivary gland.

Differentiation-inducing factor 1 [DIF-1; 1-(3,5-dichloro-2,6-dihydroxy-4-methoxyphenyl) hexan-1-one] from Dictyostelium discoideum exhibits antiproliferative activity in mammalian cells. We have previously shown that phosphodiesterase 1 (PDE1) is a pharmacological target of DIF-1, but there are no reports of PDE1 in human malignant melanoma cells. Therefore, we characterized PDE1 in human malignant melanoma MAA cells.PDE1 mRNA expression was investigated in MAA cells. The full open reading frames for human PDE1C1 and PDE1C3 were cloned. Cell growth was determined by MTS [3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2H-tetrazolium, inner salt] assay.PDE1C mRNA expression was detected in MAA cells. The nucleotide sequence of PDE1C1 was identical to that of human PDE1C1, previously published. At nucleotide 2246 in PDE1C3, A was replaced by G, but this did not change the encoded amino acid. Cell growth was inhibited by the PDE1 inhibitor vinpocetin.PDE1C mRNA is expressed and may play an important role in human malignant melanoma MAA cells.

The activity, expression and function of phosphodiesterase 4 (PDE 4) were investigated in the HMG human gingiva-derived malignant melanoma cell line. A specific PDE4 inhibitor, rolipram, inhibited PDE activity in homogenates of HMG cells, and PDE4B and 4D mRNAs were detected by RT-PCR in RNA from HMG cells. Two specific PDE4 inhibitors, rolipram and Ro-20-1724, and an adenylate cyclase activator, forskolin, increased intracellular cAMP in HMG cells. Cell growth induced by rolipram, Ro-20-1724, and forskolin was inhibited by the H-89 protein kinase A (PKA) inhibitor. However, in contrast to effects of H-89, two other PKA inhibitors, KT5720 and PKI, did not inhibit rolipram-induced cell growth. A cAMP analogue that selectively activates Epac, 8-pCPT-2'-O-Me-cAMP, also promoted the growth of HMG cells. These findings suggested that PDE4, PDE4B and/or 4D regulate cell growth through cAMP targets in the HMG malignant melanoma cell line. There have been no previous studies of positive regulation of cell growth by PDE4 inhibition, suggesting that it may be possible to target PDE4 in therapy for human malignant melanoma.

The differentiation-inducing factor-1 (DIF-1) isolated from Dictyostelium discoideum is a potent antiproliferative agent that induces growth arrest and differentiation in mammalian cells in vitro. However, the specific target molecule(s) of DIF-1 has not been identified. In this study, we have tried to identify the target molecule(s) of DIF-1 in mammalian cells, examining the effects of DIF-1 and its analogs on the activity of some candidate enzymes. DIF-1 at 10–40 μm dose-dependently suppressed cell growth and increased the intracellular cyclic AMP concentration in K562 leukemia cells. It was then found that DIF-1 at 0.5–20 μm inhibited the calmodulin (CaM)-dependent cyclic nucleotide phosphodiesterase (PDE1) in vitro in a dose-dependent manner. Kinetic analysis revealed that DIF-1 acted as a competitive inhibitor of PDE1 versus the substrate cyclic AMP. Because DIF-1 did not significantly affect the activity of other PDEs or CaM-dependent enzymes and, in addition, an isomer of DIF-1 was a less potent inhibitor, we have concluded that PDE1 is a pharmacological and specific target of DIF-1.

We have evaluated effects of a phosphodiesterase (PDE) 4 inhibitor on retinoic acid-increased alkaline phosphatase activity in the mouse fibroblastic C3H10T1/2 clone 8 (10T1/2) cell line. 10T1/2 cells were cultured in minimum essential medium (MEM) and 10% fetal bovine serum with or without 1 microM retinoic acid and/or the PDE 4 inhibitor, rolipram, and harvested at specific intervals before measurement of alkaline phosphatase activity, cAMP production in response to parathyroid hormone, osteocalcin synthesis and expression, and phosphodiesterase activity. Retinoic acid-increased alkaline phosphatase activity, and slightly enhanced cAMP production in response to parathyroid hormone. However, it did not affect osteocalcin synthesis and expression. In the presence of retinoic acid, PDE 4 activity was not changed. A PDE 4 inhibitor, rolipram, and cAMP analog, 8-bromo-cAMP dramatically increased retinoic acid's ability to induce alkaline phosphatase activity. This is the first report that PDE 4 may be involved in regulation of retinoic acid-increased alkaline phosphatase activity.

Little is known concerning the expression, distribution and function of phosphodiesterase (PDE) 3s in malignant tumor cells, including human malignant melanoma HMG and osteosarcoma HOSM-1 cells. PDE3 activity was detected in homogenates of HMG cells; however, much less activity was found in HOSM-1 cells. In HMG cells, most of the PDE3 activity was in the particulate fraction. PDE3A and 3B mRNAs were detected by RT-PCR in RNA from HMG cells only. The nucleotide sequences of the fragments were identical to those of human PDE3A and 3B. The PDE3-specific inhibitors, trequinsin and cilostamide, did not inhibit the proliferation of HMG or HOSM-1 cells. Although two PDE3 isoforms may be expressed in human malignant melanoma cells, their functional importance is not known.