Long Lasting Efficiency of Monthly Vinblastine in a Case of Relapsed Anaplastic Large Cell Lymphoma

Nearly 40% of children with Anaplastic Large cell lymphomas will relapse after a first-line strategy with short-pulse chemotherapy and reach a second remission in 30% to 60% with second line therapies including maintenance treatment with vinblastine or allogeneic hematopoietic stem-cell transplantation. The authors report a heavily pretreated case in second relapse who was maintained in third remission for 8 years with monthly vinblastine. He relapsed 16 weeks after discontinuation. This case demonstrates that monthly treatment with vinblastine may be sufficient to maintain a minimal disease. Oral compounds are now available and should be discussed in such situations.

Synthesis of molecularly imprinted polymers for the application of selective clean-up vinblastine from Catharanthus roseus extract

Molecularly imprinted polymers (MIPs) are synthetic tailor-made polymers with high selectivity towards a particular substance (template).An MIP using vinblastine (VLB) as the template molecule was synthesized and characterized.The presence of monomer-template complexes in a non-covalent way was confirmed by UV-vis spectrometry analysis.The polymerization was performed using methacrylic acid (MAA) as the functional monomer,ethylene glycol dimethacrylate (EGDMA) as the cross-linking agent,and toluene as the porogenic solvent by a thermo-polymerization method.The characterization of the obtained MIP was evaluated by scanning electron microscopy (SEM) and Brunauer-Emmett-Teller (BET) analysis.It was observed that the morphology of the MIP was more porous and rough,and the surface area had a significant increase compared with that of the non-imprinted polymer (NIP).This MIP was used as the sorbents of solid-phase extraction (SPE) to assess the selectivity of the MIP after optimization of the SPE protocol.VLB was specifically adsorbed on the MIP cartridge,while to vincristine (VCR),the chemical analog of VLB,almost no selective binding appeared.On the basis of the results,Catharanthus roseus extract was applied to the MIP cartridge for investigating its capability to extract VLB from the plant extract,and the capacity of the MIP cartridge was also evaluated.It was shown that the MIP could effectively enrich VLB from C.roseus extract and the recovery amounted to 93.8%.The solvents dissolving the samples had significant influence on the capacity of the MIP cartridge;it was 750 μg/g in toluene,625 μg/g in chloroform,and 250 μg/g in methanol.

Mechanical properties of hepatocellular carcinoma cells

AIM: To study the viscoelastic properties of human hepatocytes and hepatocellular carcinoma (HCC) cells under cytoskeletal perturbation, and to further to study the viscoelastic properties and the adhesive properties of mouse hepatoma cells (HTC) in different cell cycle. METHODS: Micropipette aspiration technique was adopted to measure viscoelastic coefficients and adhesion force to collagen coated surface of the cells. Three kinds of cytoskeleton perturbing agents, colchicines (Col), cytochalasin D (CD) and vinblastine (VBL), were used to treat HCC cells and hepatocytes and the effects of these treatment on cell viscoelastic coefficients were investigated. The experimental results were analyzed with a three-element standard linear solid. Further, the viscoelastic properties of HTC cells and the adhesion force of different cycle HTC cells were also investigated. The synchronous G(1) and S phase cells were achieved through thymine-2-desoryriboside and colchicines sequential blockage method and thymine-2-desoryriboside blockage method respectively. RESULTS: The elastic coefficients, but not viscous coefficient of HCC cells (K(1)=103.6+/-12.6N.m(-2), K(2)=42.5 +/ 10.4N.m(-2), mu=4.5 +/- 1.9Pa.s), were significantly higher than the corresponding value for hepatocytes (K(1)=87.5 +/- 12.1N.m(-2), K(2)=33.3+/-10.3N.m(-2), mu=5.9+/-3.0Pa.s, P【0.01). Upon treatment with CD, the viscoelastic coefficients of both hepatocytes and HCC cells decreased consistently, with magnitudes for the decrease in elastic coefficients of HCC cells (K(1): 68.7 N.m(-2) to 81.7N.m(-2), 66.3% to 78.9%; K(2): 34.5N.m(-2) to 37.1N.m(-2), 81.2% to 87.3%, P【0.001) larger than those for normal hepatocytes (K(1): 42.6N.m(-2) to 49.8N.m(-2), 48.7% to 56.9%; K(2): 17.2N.m(-2) to 20.4N.m(-2), 51.7% to 61.3%, P【0.001). There was a little decrease in the viscous coefficient of HCC cells (2.0 to 3.4Pa.s, 44.4 to 75.6%, P【0.001) than that for hepatocytes (3.0 to 3.9Pa.s, 50.8 to 66.1% P【0.001). Upon treatment with Col and VBL, the elastic coefficients of hepatocytes generally increased or tended to increase while those of HCC cells decreased. HTC cells with 72.1% of G(1) phase and 98.9% of S phase were achieved and high K(1), K(2) value and low mu value were the general characteristics of HTC cells. G(1) phase cells had higher K(1) value and lower mu value than S phase cells had, and G(1) phase HTC cells had stronger adhesive forces ((275.9 +/- 232.8) x 10(-10)N) than S phase cells ((161.2 +/- 120.4) x 10(-10)N, P【0.001). CONCLUSION: The difference in both the pattern and the magnitude of the effect of cytoskeletal perturbing agent on the viscoelastic properties between HCC cells and hepatocytes may reflect differences in the state of the cytoskeleton structure and function and in the sensitivity to perturbing agent treatment between these two types of cells. Change in the viscoelastic properties of cancer cells may affect significantly tumor cell invasion and metastasis as well as interactions between tumor cells and their micro-mechanical environments.

Molecularly imprinted nanoparticles and their releasing properties, bio-distribution as drug carriers

Molecular imprinted nanoparticles(MINPs) can memorize the shape and functional group positions complementary to template, which account for the large drug loading capacity and slow drug release behavior as drug carriers. We synthesized MINPs via precipitation polymerization with vinblastine(VBL) as a model drug, and investigated the drug loading,releasing property in vitro and bio-distribution in vivo. The obtained MINPs, from 300 to 450 nm,had smooth surface and favorable dispersibility. The entrapment efficacy and drug loading capacity of VBL loaded MINPs(MINPs-VBL) were 83.25% and 8.72% respectively. In PBS(pH 7.4),MINPs-VBL showed sustained release behavior. The cumulative release percentage reached about 70% during 216 h and no burst release was observed. The releasing behavior of MINPsVBL in vitro conformed to the first-order kinetics model. MINPs-VBL and commercially available vinblastine sulfate injection(VBL injection) were injected via tail vein of SD rats respectively to investigate the bio-distribution. MINPs-VBL group showed higher concentration of VBL in tissues and serum than VBL injection group after 60 min, and the drug level in liver was the highest. MINPs-VBL exhibited liver targeting trend to some extent, which was based on the evaluation of drug targeting index(DTI) and drug selecting index(DSI).

Non-AIDS-related Kaposi’s sarcoma:A single-institution experience

AIM:To evaluate the outcomes and potential prognostic factors in patients with non-acquired immunodeficiency syndrome(AIDS)-related Kaposi’s sarcoma(KS).METHODS:Patients with histologically proven non-AIDS-related KS treated with systemic chemotherapy were included in this retrospective analysis.In some cases,the human herpes virus 8 status was assessed by immunohistochemistry.The patients were staged according to the Mediterranean KS staging system.A multivariable model was constructed using a forward stepwise selection procedure.A P value<0.05 was considered statistically significant,and all tests were two-sided.RESULTS:Thirty-two cases were included in this analysis.The average age at diagnosis was 70 years,with a male/female ratio of approximately 2:1.Eighty-four percent of the cases had classic KS.All patients received systemic chemotherapy containing one of the following agents:vinca alkaloid,taxane,and pegylated liposomal doxorubicin.Ten patients(31.5%)experienced a partial response,and a complete response was achieved in four patients(12.4%)and stable disease in sixteen cases(50%).Two patients(6.2%)were refractory to the systemic treatment.The median progression-free survival(PFS)was 11.7 mo,whereas the median overall survival was 28.5 mo.At multivariate analysis,the presence of nodular lesions(vs macular lesions only)was significantly related to a lower PFS(hazard ratio:3.09;95%CI:1.18-8.13,P=0.0133).CONCLUSION:Non-AIDS-related KS appears mostly limited to the skin and is well-responsive to systemic therapies.Our data show that nodular lesions may be associated with a shorter PFS in patients receiving chemotherapy.

GENE EXPRESSION PROFILING IN MULTIDRUG RESISTANT KB CELLS USING cDNA MICROARRAYS

Objective: A single mechanistic pathway cannot explain the genesis of drug resistance in cancer. Drug resistance in cancer is a major obstacle to successful chemotherapy. KB cells provide a useful starting point for selection of the multidrug resistant (MDR) cell lines. Methods: We used cDNA microarrays containing 12,720 sequences of known genes, expressed sequence tags and unknown clones to monitor gene expression profiles in MDR KB cells. Results: Preliminary data analysis showed that 18 genes were up-regulated and 18 genes were down-regulated by comparison of expression patterns between KB 3-1 and MDR KB-V1 cells. Furthermore, the highly over-expressed CGA, CLU genes in MDR KB-V1 cell were verified with conventional Northern blot analysis. These genes contain information predictive of drug resistance of cancer cells. Conclusion: Our study demonstrates that genome-wide gene expression profiling by using cDNA microarray technique is a valuable approach in obtaining molecular mechanism of drug resistance in cancer cells.

Biosynthetic pathway of terpenoid indole alkaloids in Catharanthus roseus

Catharanthus roseus is one of the most extensively investigated medicinal plants, which can produce more than 130 alkaloids, including the powerful antitumor drugs vinblastine and vincristine. Here we review the recent advances in the biosynthetic pathway of terpenoid indole alkaloids （TIAs） in C. roseus, and the identification and characterization of the corresponding enzymes involved in this pathway. Strictosidine is the central intermediate in the biosynthesis of different TIAs, which is formed by the condensation of secologanin and tryptamine. Secologanin is derived from terpenoid （isoprenoid） biosynthetic pathway, while tryptamine is derived from indole biosynthetic pathway. Then various specific end products are produced by different routes during downstream process. Although many genes and corresponding enzymes have been characterized in this pathway, our knowledge on the whole TIA biosynthetic pathway still remains largely unknown up to date. Full elucidation of TIA biosynthetic pathway is an important prerequisite to understand the regulation of the TIA biosynthesis in the medicinal plant and to produce valuable TIAs by synthetic biological technology.

The FAPα-activated prodrug Z-GP-DAVLBH inhibits the growth and pulmonary metastasis of osteosarcoma cells by suppressing the AXL pathway

Osteosarcoma is a kind of bone tumor with highly proliferative and invasive properties,a high incidence of pulmonary metastasis and a poor prognosis.Chemotherapy is the mainstay of treatment for osteosarcoma.Currently,there are no molecular targeted drugs approved for osteosarcoma treatment,particularly effective drugs for osteosarcoma with pulmonary metastases.It has been reported that fibroblast activation protein alpha(FAPa)is upregulated in osteosarcoma and critically associated with osteosarcoma progression and metastasis,demonstrating that FAPa-targeted agents might be a promising therapeutic strategy for osteosarcoma.In the present study,we reported that the FAPa-activated vinblastine prodrug Z-GP-DAVLBH exhibited potent antitumor activities against FAPa-positive osteosarcoma cells in vitro and in vivo.Z-GP-DAVLBH inhibited the growth and induced the apoptosis of osteosarcoma cells.Importantly,it also decreased the migration and invasion capacities and reversed epithelial-mesenchymal transition(EMT)of osteosarcoma cells in vitro and suppressed pulmonary metastasis of osteosarcoma xenografts in vivo.Mechanistically,Z-GP-DAVLBH suppressed the AXL/AKT/GSK-3β/β-catenin pathway,leading to inhibition of the growth and metastatic spread of osteosarcoma cells.These findings demonstrate that Z-GP-DAVLBH is a promising agent for the treatment of FAPa-positive osteosarcoma,particularly osteosarcoma with pulmonary metastases.

Current advances in Hodgkin’s lymphoma

Hodgkin’s lymphoma is a highly treatable malignancy. It has high cure rates yet there are many patients who relapse or are refractory to treatment. Traditionally, treatment has been with conventional chemotherapy;however, the development of brentuximab vedotin and immune checkpoint inhibitors has revolutionized the care of Hodgkin’s lymphoma. This is a review of the current advances in the management of Hodgkin’s lymphoma and a review of ongoing clinical trials in the field.

Bioproduction of monoterpene indole alkaloids in a single cell factory

The de novo biosynthesis of vindoline and catharanthine,the direct precursors used for industrial production of the anti-cancer drug vinblastine,has been achieved in the yeast cell factory.To date,this is the longest natural product biosynthesis pathway that has been successfully transferred from plants to microorganisms,indicating the possibility of producing more than 3,000 other monoterpene indole alkaloids in yeast by synthetic genome engineering.