Biomedical subjects

Peng Liu

Publications and source records attributed to Peng Liu.

At least 91 records · Page 5Linked to original sources

PubMed2004

Modified U1 snRNA suppresses expression of a targeted endogenous RNA by inhibiting polyadenylation of the transcript.

We have previously demonstrated that a modified U1 snRNA inhibits expression of a number of targeted transgenes. Here we exploit the ability of the modified U1 snRNA to inhibit endogenous gene expression and define the mechanism responsible for this inhibitory action. MC3T3-E1 cells stably transfected with U1 anti-Cbfa1 show a change of morphology from polygonal to fibroblast-like cells. This visual observation was supported by an 80% reduction of Cbfa1 expression and suppression of downstream genes associated with osteoblast differentiation. In rat ROS 17/2.8 cells, osteocalcin and Col1a1 gene expression was reduced up to 90% by the U1 anti-osteocalcin or U1 anti-Col1a1 construct, respectively. The length of mature osteocalcin mRNA poly(A) tail was significantly shortened in the targeted mRNA by transcript-specific poly(A) test (PAT)-PCR. These data demonstrate that the modified U1 snRNA is able to reduce endogenous gene expression by limiting the polyadenylation of the targeted pre-mRNA transcript.

Animals↗

PubMed2004

Study on biological effect of La3+ on Escherichia coli by atomic force microscopy.

The biological effects of rare-earth metal ions on the organism have been studied using La3+ as a probe ion and Escherichia coli cell as a target organism. Atomic force microscopy (AFM) studies reveal that La3+ substantially changes the structure of the outer cell membrane responsible for the cell permeability. Significant damages of the outer cell membrane are observed using scanning electron microscopy (SEM) after the introduction of La3+. In result, the cell becomes easily attacked by lysozyme. Moreover, inductively coupled plasma-mass spectrometry (ICP-MS) measurements show considerable amount of Ca2+ and Mg2+ in the supernatant from the La3+ exposed cells. It is proposed that La3+ can replace Ca2+ from the binding sites because of their close ionic radii and similar ligand specificities. Lipopolysaccharide (LPS), which forms the outer membrane of Gram-negative bacteria, could not serve as the cellular envelope steadily after Ca2+ and Mg2+ released from their binding sites on the LPS patches.

Calcium↗

PubMed2004

Reversal of P-glycoprotein-mediated multidrug resistance with small interference RNA (siRNA) in leukemia cells.

The multidrug resistance (MDR) mediated by P-glycoprotein (P-gp), the MDR1 gene product, is one of the major obstacles in leukemia treatment. The present study was designed to explore a MDR1-targeted small interfering RNA (si-MDR1) approach for reversal of P-gp-mediated MDR in the MDR human leukemia cell line k562/A02. It was found that si-MDR1 significantly inhibited MDR1 expression at both mRNA and protein levels. Depletion of MDR1 by si-MDR1 correlated with the increased sensitivity of the cells to cytotoxic agents and with the enhanced intracellular retention of daunorubicin (DNR). One base-pair mutated control (si-MDR1-Mut) lost the effect of si-MDR1 on both the degradation of mdr1 mRNA and the reduction of P-gp expression. These findings indicate that siRNA specifically and efficiently interferes with the expression of mdr1 and could be used as a molecularly defined therapeutic approach for MDR in the treatment of leukemia.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

[Reversal of multi-drug resistance in K562/A02 cells by small interference RNA of mdr1 gene].

OBJECTIVE: To investigate the effect of small interference RNA (siRNA) on mdr1 and P-glyco-protein (P-gp) expression of multi-drug resistance (MDR) human leukemia cell line K562/A02. METHODS: Three si RNAs (si-mdr1-1, si-mdr1-2, si-mdr1-3) which were specifically targeted mdr1 gene were synthesized and transfected into K562/A02 cells. Expression of mdr1 mRNA was assayed by RT-PCR. P-gp expression and intracellular daunorubicin (DNR) concentration were determined by flow cytometry. 50% inhibition concentration (IC(50)) of doxorubicin (ADM) on K562/A02 was determined by MTT method. RESULTS: Treatment of K562/A02 cell with the 3 kinds of siRNAs resulted in a reversal of MDR of a different extent. The third siRNA was more effective in the suppression of mdr1 with a significant reduction of (58.0 +/- 1.54)% of the mdr1 mRNA expression. Positive expression rate of p170 decreased from (76.0 +/- 1.0)% to (19.6 +/- 1.9)%, and the relative efficiency of K562/A02 to ADM was 70.4%. The intracellular accumulation of DNR increased after siRNA treatment. CONCLUSION: The siRNA could effectively restore the sensitivity of K562/A02 cells to conventional chemotherapeutic agents.

Base Sequence↗

PubMed2004

[Clinical evaluation of effects from neoadjuvant chemotherapy with epirubicin plus paclitaxel in cases of locally advanced breast cancer--comparative study of treatment with 2 and 4 cycles].

Neoadjuvant chemotherapy of epirubicin plus paclitaxel was administered to 75 patients (including a 2-cycle group of 39 patients and a 4-cycle group of 36 patients) with locally advanced breast cancer (35 cases of stage IIb, 28 of stage IIIa, 12 of stage IIIb) to compare efficacy and toxicity of 2 cycle and 4 cycle regimens. All patients were female. They were treated with epirubicin 60 mg/m2, on day 1, by i.v., followed by paclitaxel 150 mg/m2, by 3 hour continuous infusion on day 2 repeated every 3 weeks. Premedication with dexamethasone, ondansetron, diphenhydramine and cimetidine were administered to prevent gastroenteritic and allergic reactions before chemotherapy. Thirty-nine patients were given 2 cycles and thirty-six were given 4 cycles of this regimen. One of 39 patients had complete response, 28 had partial response and 10 had no change in the 2-cycle group. In addition, 21 of 36 patients had complete response (including 9 who had pathologic complete response), 13 had partial response and 2 had no change. The response rates were 74% (29/39) in the 2-cycle group and 94% (34/36) in the 4-cycle group. There were no progressive disease in these 2 groups. However a higher proportion of PR was observed in stage II patients than in stage III patients. Twelve of 36 patients underwent breast conserving surgery, as tumor size had become smaller and down-staging was realized after neoadjuvant chemotherapy. In addition, axillary lymph nodes were palpable in all 75 patients before neoadjuvant chemotherapy with the ET regimen. But 46% (18/39) in the 2-cycle group and 75% (27/36) in the 4-cycle group became impalpable. Conversely, major toxicities (including leukopenia and gastroenteric reactions) were similar in both groups, but myalgia, arthralgia, neurotoxicity and alopecia were more severe in the 4-cycle group than in the 2-cycle group. In the present study, neoadjuvant chemotherapy with a 4-cycle ET regimen was more effective than with a 2-cycle regimen in down staging locally advanced breast cancer. Although major toxicities were more severe in the 4-cycle group than in the 2-cycle group, the regimen was tolerable and safe.

Adult↗

PubMed2004

[Tropisetron in attenuation of nausea and vomiting in patients undergoing high-dose chemo-radiotherapy supported by autologous peripheral blood stem cell transplantation].

BACKGROUND & OBJECTIVE: High-dose conditioning regimens of chemo-radiotherapy with or without total body irradiation (TBI) frequently induces nausea and vomiting in patients who are supported with stem cell transplantation. 5-Hydroxytrypamine(3) (5-HT(3)) receptor antagonists, when used alone, are unsatisfactory in the attenuation of emesis; Furthermore, consensus about their optimal dose, optimal dosing frequency and the combined use with other anti-emetic drugs are still controversial. The main objective of this trial was to observe the anti-emetic effectiveness and side effects of tropisetron plus dexamethasone and diphenhydramine (Group A) and tropisetron alone (Group B) on the patients undergoing high-dose treatment for peripheral blood stem cell (PBSC) mobilization and transplantation. METHODS: From December 1998 to September 2002, 68 patients undergoing autologous peripheral blood stem cell transplantation were allotted into this study. All the eligible patients were divided into group A or B non-randomly to compare the efficacy of the two regimens in the prevention of nausea and vomiting induced by high-dose treatment. Regimens:40 patients in group A were given tropisetron 5 mg,iv,every 12 h plus dexamethasone 5-10 mg, iv, daily, and diphenhydramine, 20 mg, im, daily. Twenty-eight patients in group B were received tropisetron alone,5 mg,iv,every 12h. RESULTS: For nausea during the acute phase, complete response rates of group A and B were 55% and 46.4%, with an overall response rates of 97.5% and 85.7%,of which the difference was insignificant (P >0.05). For vomiting during the acute phase, complete response rates of group A and B were 77.5% and 78.6%, with an overall response rates of 90% and 92.9%, of which the difference was insignificant (P >0.05). For delayed phase, both the complete response and overall response rates were higher in group A, with the difference significant (P< 0.05). The side effects of both regimens were mild. Common side effects including abdomen discomfort,headache,heavy head and constipation did not necessitate the discontinuity of high-dose treatment. CONCLUSION: The combination of tropisetron with dexamethasone and diphenhydramine is more effective than tropisetron alone in the control of nausea and vomiting induced by high-dose chemotherapy with or without TBI, which is especially more effective in the delayed phase of nausea and vomiting. The side effects of the combination regimen were mild. Based on these findings, we stress the importance of large randomized trials in the future.

Adolescent↗

PubMed2004

[Mobilization of autologous peripheral blood stem cells with etoposide and recombinant human granulocyte colony stimulating factor in malignant tumor patients].

OBJECTIVE: To observe the combined effect of etoposide (Vp-16) and recombinant human granulocyte colony-stimulating factor (rhG-CSF) on mobilization of autologous peripheral blood stem cells (APBSC) in malignant tumor patients and find out the suitable dose of Vp-16. METHODS: Thirty patients were randomly divided into two groups, 15 in each group. In group A, Vp-16 1000 mg/m(2) was injected intravenously in six divided doses, for 2 hours every 12 hours on day 1, 2 and 3. In group B, Vp-16 1500 mg/m(2) was injected intravenously in six divided doses for 3 hours every 12 hours on day 1, 2 and 3. rhG-CSF was given as a single daily injection subcutaneously at the dose of 300 microg.body(-1).day(-1) from the day of the nadir of white blood cell (WBC) to the day before the end of APBCS harvest. APBSC harvest started when WBC > or = 5.0 x 10(9)/L and finished when accumulated mononuclear cells (MNC) > or = 5 x 10(8)/kg or CD34+ cells > or = 2 x 10(6)/kg. RESULTS: There was no significant difference between the time of nadir, nadir of WBC, absolute neutrophil count (ANC), the beginning time and continuous time of rhG-CSF given, the beginning time and continuous time of APBSC harvest. When the blood volume, flow rate and continuous time of apheresis were similar in each apheresis in the two groups, the number of APBSC in each harvest and total number of APBSC were also not significantly different between the two groups. The side effects induced by Vp-16 were also not significant different between the two groups. CONCLUSION: Vp-16 combined with rhG-CSF is a safe and highly effective method for APBSC mobilization, 1000 mg/m(2) and 1500 mg/m(2) of Vp-16 possess similar efficiency and side effects for APBSC mobilization.

Adolescent↗

PubMed2004

[Comparison between tow methods of acute physiology and chronic health evaluation III and acute lung injury scale to evaluate the severity and prognosis of severe acute respiratory syndrome].

OBJECTIVE: To evaluate the acute physiology and chronic health evaluation III (APACHE III) and acute lung injury (ALI) scale in the severity and prognosis of severe acute respiratory syndrome (SARS). METHODS: The clinical data of 38 SARS patients, including survivors (24 cases) and no survivors (14 cases) were collected and evaluated with APACHE III and ALI scoring systems. The correlation of scores and prognosis was evaluated. RESULTS: The scores of APACHE III in the non survivors were higher remarkably than those in the survivor group (P < 0.001). The scores of APACHE III had positive correlation with the overall fatality rate. When the scores of APACHE III was higher than 60, the mortality increased obviously (chi(2) = 3.886, P < 0.05). Elderly patients with SARS who were over 60 years old had a high mortality (chi(2) = 8.660, P < 0.05). The scores of ALI in the non survivors had not statistical significance than those in the survivor group (P = 0.127). CONCLUSIONS: The score of APACHE III in the SARS are correlated with the patient's condition and prognosis. Elderly patients with SARS have a high mortality.

APACHE↗

PubMed2004

[Expression of angiogenic factors and their clinical significances in acute myeloid leukemia].

BACKGROUND & OBJECTIVE: To investigate the expression of vascular endothelial growth factor (VEGF) & basic fibroblast growth factor (bFGF) in primary acute myeloid leukemia (AML) cells, and study plasma VEGF& bFGF concentration in patients with AML and the two factors' clinical significance. METHODS: VEGF&bFGF and their receptors mRNA expression were detected by RT-PCR; VEGF & bFGF plasma level was analyzed by ELISA. RESULTS: In 107 AML patients, the positive mRNA expression rate of VEGF, KDR and Flt1 was 56.1%, 49.5%, and 2.8%, respectively; for bFGF and FGFR1-4, the positive rate was 21.5%, 35.5%, 9.4%, 35.5% and 23.4%, respectively. VEGF concentration in AML (154.75+/-109.98) pg/ml was significantly higher than that in AML-CR (72.05+/-23.39) pg/ml and the normal control (99.91+/-41.87) pg/ml (P< 0.05). Nevertheless, the level of bFGF had no significant difference among AML, AML-CR and the normal control. VEGF level (124.05+/-76.57) pg/ml in patients, who got complete remission (CR) after 2 cycles of chemotherapy, was remarkably lower than that (211.243+/-169.88) pg/ml in patients without CR (P< 0.05). Furthermore, the higher the concentration of VEGF & bFGF, the shorter the survival was. CONCLUSION: VEGF& bFGF and their receptors mRNA in leukemic patients could be expressed to some degree,and our investigation suggested VEGF &bFGF and their receptors probably be produced by autocrine or paracrin. Abnormally high level of VEGF may be a poor factor for chemotherapy and survival in AML. The prognosis of patients with AML may be improved by treating VEGF and their receptors as therapy targets.

Acute Disease↗

PubMed2004

[Experimental study of a biological dural graft in rabbits].

OBJECTIVE: To evaluate the safety and efficacy of a dural graft prepared using porcine membrane in duraplasty. METHODS: Eighteen New Zealand rabbits were randomly divided into groups A (n=4), B (n=4), C (n=5), and D (n=5) sacrificed 3, 14, 30 and 90 d after duraplasty, respectively. Each animal underwent bilateral parietal craniectomy behind the coronal suture and beside the midline to expose the dura, which was cut on the right side and substituted with the dural graft. The exposed dura on the left was kept intact as control. The rabbits were observed for WBC counts before the operation and before sacrifice by transcardiac formalin perfusion, respectively. The meninges and brain tissues were histologically examined after sacrifice. RESULTS: The WBC count varied little after the operation (P>0.05). Microscopic examination demonstrated tissue repair on both the implantation side and control side, without graft adhesion to the cortical surface. In group A, a large number of leukocytes were seen gathering on the lateral dura, suggesting acute tissue repair. In group B, endothelial cells covering the inner surface of the graft could be seen. Fibroblasts and fibrocytes were seen in the grafts between collagen fibers in group C, and in group D, fibroblasts and fibrocytes increased between the collagen fibers and the suture healed. CONCLUSION: The dura graft is safe and applicable for dural defect repair.

Animals↗

PubMed2004

[Expression of adhesion molecules on CD34+ cells of BM and PB stem cell samples during high-dose chemotherapy combined with transplantation of autologous PB stem cells].

This study was aimed to investigate the expressions of adhesion molecules such as CD54, CD49d and CD62L by CD34(+) cells sampled from different stages of bone marrow (BM) and peripheral blood (PB) before/after G-CSF mobilization and after transplantation through the direct labeling with three colour-immunofluorescence and flow cytometry, and to explore the differences in expression of adhesion molecules on CD34(+) cells from different origins and their clinical significance. Mononuclear cells collected from BM and PB before mobilization, after collection of stem cells and hematopoietic recostruction of BM at the end of transplantation were marked with CD54-FITC, CD49d-FITC and CD62L-FITC separately, as well as CD34-PE and CD45PerCE. 3-color fluorescene analysis was carried out by FACS. The expression differences of CD34(+) and adhesion molecules between BM and APBSC were compared. The results showed that expression differences of CD54, CD49d and cd62Lon CD34(+) cells belore mobilization, after collection and reconstraction of transplantation were not statiscally significant, the difference of CD54, CD49d and CD62L on CD34(+) between 1st and 2nd collections of hematopoietic stem cells also were not statiscally significant. In the collected APBSC, the expression level of CD34(+) CD49d(+) was significantly lower than those in BM before mobilization (P = 0.001). It is concluded that the method of chemotherapy combined with G-CSF mobilization can down-regulate CD49d expression in BM CD34(+) cells, thus can mobilize and move theirs into peripheral blood. After the reconstitution by transplantation, the expression of CD49d on CD34(+) cells tends to normal, the clinical significance needs to be elucidated by accumulation of much more cases.

Adolescent↗

PubMed2004

The distribution of six biallelic polymorphisms on non-recombining segments of the Y-chromosome in five Chinese populations.

Ancient demographic events can be inferred from the distribution of biallelic polymorphisms of NRY. In our study, six Y-biallelic markers were screened in 326 Y-chromosomes from five Chinese populations: Manchu, Fujian Han, Kazak, Bouyei and Sichuan Han. The chi2-test was performed using the SAS package. ARLEQUIN and SPSS programs were used for pairwise Fst's and genetic clusters, respectively. The M9 (G) and RPS4Y (T) polymorphisms show greater variance in these five populations and are informative and sensible in Chinese population genetic research, while the other four are less polymorphic. Significant differences in the distribution of the six biallelic markers were found between the three southern groups and the two northern groups involved in the present study. The Kazak population demonstrated marked differences not only from the southern populations, but differed notably from the other northern population, the Manchu. This result clearly suggests that the original division of the investigated groups into north and south would not yield optimal results from which useful generalizations could be made. The results have proven to be extremely useful, their analysis not only brought to light important new facts on the population structures, but supplied also useful guidelines for further additional Chinese population genetic research projects.

Alleles↗

PubMed2003

[Efficacy of gamma knife radiosurgery in treatment of growth hormone-secreting pituitary adenoma].

OBJECTIVE: To evaluate the efficacy of gamma knife radiosurgery (GKS) in treatment of growth hormone (GH)-secreting pituitary adenoma. METHODS: 149 patients with GH-secreting pituitary adenoma, 97 males and 52 females, aged 42.8 (12-72 years), with a course of 6-240 months (72.5 months) and with the mean volume of tumor of 2.36 cm(3) (0.11-12.7 cm(3)) were treated by GKS. The mean dose to tumor margin was 20.87 Gy (10-30 Gy). 124 of them were followed up for 30 months (6-72 months). RESULTS: The serum GH returned normal in 74 patients (64.9%) and declined in comparison with the level before radiosurgery in 23 patients (18.5%). The tumor volume was reduced in 84 patients (67.7%) and remained unchanged in 124 patients (32.4%). Ambiopia appeared in one patient. No other complication was found during the follow-up. CONCLUSION: GKS is safe and effective on the treatment of GH-secreting pituitary adenoma.

Adenoma↗

PubMed2003

Practical synthesis of D- and l-2-cyclopentenone and their utility for the synthesis of carbocyclic antiviral nucleosides against orthopox viruses (smallpox, monkeypox, and cowpox virus).

Highly efficient and practical methodology for the syntheses of D- and l-4,5-O-isopropylidene-2-cyclopentenone (9 and 22), versatile intermediates for the synthesis of carbocyclic nucleosides, have been developed via a ring-closing metathesis reaction from d-ribose in eight steps. The utility of D- and l-4,5-O-isopropylidene-2-cyclopentenone is demonstrated by their application for the preparation of D-cyclopentyl-6-azauridine 12 and D-cyclopentenyl-5-halocytosine nucleosides (33-35) using Mitsunobu reaction to introduce pyrimidine bases as potential antiviral agents. Preliminary antiviral activity against orthopox viruses (smallpox, monkeypox, and cowpox virus) of the synthesized nucleosides are described.

Antiviral Agents↗

PubMed2003

Inhibiting expression of specific genes in mammalian cells with 5' end-mutated U1 small nuclear RNAs targeted to terminal exons of pre-mRNA.

Reducing or eliminating expression of a given gene is likely to require multiple methods to ensure coverage of all of the genes in a given mammalian cell. We and others [Furth, P. A., Choe, W. T., Rex, J. H., Byrne, J. C., and Baker, C. C. (1994) Mol. Cell. Biol. 14, 5278-5289] have previously shown that U1 small nuclear (sn) RNA, both natural or with 5' end mutations, can specifically inhibit reporter gene expression in mammalian cells. This inhibition occurs when the U1 snRNA 5' end base pairs near the polyadenylation signal of the reporter gene's pre-mRNA. This base pairing inhibits poly(A) tail addition, a key, nearly universal step in mRNA biosynthesis, resulting in degradation of the mRNA. Here we demonstrate that expression of endogenous mammalian genes can be efficiently inhibited by transiently or stably expressed 5' end-mutated U1 snRNA. Also, we determine the inhibitory mechanism and establish a set of rules to use this technique and to improve the efficiency of inhibition. Two U1 snRNAs base paired to a single pre-mRNA act synergistically, resulting in up to 700-fold inhibition of the expression of specific reporter genes and 25-fold inhibition of endogenous genes. Surprisingly, distance from the U1 snRNA binding site to the poly(A) signal is not critical for inhibition, instead the U1 snRNA must be targeted to the terminal exon of the pre-mRNA. This could reflect a disruption by the 5' end-mutated U1 snRNA of the definition of the terminal exon as described by the exon definition model.

3' Untranslated Regions↗

PubMed2003

[Adenoviral vector expressing an antiangiogenic fragment of thrombospondin 1 inhibits the growth of K562 cell xenografts].

OBJECTIVE: To explore the effect of adenovirus-mediated delivery of an antiangiogenic fragment of human thrombospondin 1 (TSP1(f)) on K562 cell growth in nude mice. METHODS: TSP1(f) cDNA was amplified by RT-PCR from normal human peripheral blood mononuclear cells and was used as transgene to construct a adenoviral vector (ADV-TSP1(f)). Human leukemia K562 cells were cultured and infected with ADV-TSP1(f) or ADV-LacZ. PBS was used as control. TSP1(f) expression/secretion by these infected K562 cells was demonstrated using Western blot analysis. MTT assay was performed to determine the effect of ADV-TSP1(f) infection on K562 cell growth kinetics. Eighteen female Balb/c nude mice were inoculated subcutaneously with human leukemia K562 cells. When the diameter of the tumor reached 5 approximately 7 mm the rats were randomly divided into 3 groups of 6 rats injected intratumorally with ADV-TSP1(f), ADV-LacZ, and PBS respectively. The volume of K562 xenografts was measured every three days during the 3-week treatment. By the end of the 21st day the mice were killed and the tumors were taken to undergo histological examination. The intratumoral microvessel density (MVD) was determined by immunohistochemical staining. RESULTS: TSP-1f was expressed and secreted efficiently by ADV-TSP1(f)-infected K562 cells. Three weeks after the initial treatment, the volume of K562 xenografts in the mice treated with ADV-TSP1(f), ADV-LacZ, and PBS was (1,108 +/- 179) mm(3), (4,518 +/- 452) mm(3), and (4,666 +/- 458) mm(3) respectively (P < 0.01). The number of CD31+ microvessels counted per x200 field was 34 +/- 9, 36 +/- 7, and 14 +/- 4 in the tumors treated with PBS, ADV.LacZ, and ADV.TSP-1f respectively (P < 0.001). CONCLUSION: Adenovirus-mediated TSP-1f gene transfer greatly inhibits K562-derived tumor growth and angiogenesis in mouse xenograft model, and may serve as a new therapy for hematological malignancies.

Adenoviridae↗

PubMed2003

Treatment of acute promyelocytic leukemia and other hematologic malignancies with arsenic trioxide: review of clinical and basic studies.

Acute promyelocytic leukemia (APL) is now the most potentially curable subtype of acute myeloid leukemia in adults because of the introduction of novel approaches in the management of this disease. All-trans-retinoic acid (ATRA)-based therapy is now the first-choice treatment of patients presenting with de novo APL, and clinical studies have shown that nearly all patients who receive ATRA therapy achieve complete remission. However, approximately 20% to 30% of APL patients eventually have relapses with resistance to further ATRA treatment. Arsenic trioxide (As2O3 [ATO]) has been established as highly effective therapy for patients with APL, even for those with disease refractory to ATRA. Furthermore, results of recent studies have suggested a broad therapeutic potential for ATO in the treatment of hematologic malignancies beyond APL. In this review, we discuss the clinical activity and multiple mechanisms of ATO therapy in the management of APL and other hematologic neoplasms.

Antineoplastic Agents↗

PubMed2003

Adenovirus-mediated gene therapy with an antiangiogenic fragment of thrombospondin-1 inhibits human leukemia xenograft growth in nude mice.

Recent investigations support the idea that angiogenesis is involved in the pathophysiology of leukemia. Within a given microenvironment, the angiogenic response is regulated by a delicate balance of angiogenesis inducers and inhibitors. Thrombospondin-1 (TSP-1) is a multifunctional extracellular glycoprotein showing angiostatic properties in multiple in vitro and in vivo assays. Interestingly, there is also proangiogenic domain in this complex molecule. Development of TSP-1 as an antiangiogenic drug has been hindered by multiplicity of its functional effects, difficulties in its production and its poor pharmacokinetics. The aim of the present study was to establish a recombinant adenovirus (ADV.TSP-1(f)) expressing antiangiogenic fragment of TSP-1 (TSP-1(f)), and to determine the feasibility for use of the adenovirally expressed TSP-1(f) in leukemia gene therapy. The results of this investigation showed that TSP-1(f) was expressed efficiently in adenovirus-transduced human myelogenous leukemia K562 cells. Compared to the controls, although there was almost no effect on proliferation of K562 cells in vitro, adenovirus-mediated TSP-1(f) transduction inhibited the growth of K562 xenografts dramatically. Furthermore, the microvessel density (MVD) was much lower in the ADV.TSP-1(f)-treated tumors compared to the controls. These data support the use of in vivo gene delivery approach to produce antiangiogenic fragment of TSP-1 for leukemia therapy.

Adenoviridae↗