In this study, the buffering capacity of amphiphilic pH-sensitivity copolymer poly(2-ethyl-2-oxazoline)-cholesteryl methyl carbonate (PEOZ-CHMC) was evaluated. The ammonium sulfate gradient method was used to prepare doxorubicin hydrochloride (DOX x HCl)-loaded liposomes (DOX-L), and then the post-insertion method was used to prepare PEOZ-CHMC and polyethylene glycol-distearoyl phosphatidyl ethanolamine (PEG-DSPE) modified DOX x HCl-loaded liposomes (PEOZ-DOX-L and PEG-DOX-L). The physico-chemical properties, in vitro drugs release behavior, cellular toxicity and intracellular delivery of liposomes were evaluated, separately. The results showed that PEOZ-CHMC has a satisfactory buffering capacity. The sephadex G-50 column centrifugation method and dynamic light scattering were used to determine the encapsulation efficiency (EE) and particle size of liposomes. The EE and particle size of DOX-L were (97.3 ± 1.4) % and 120 nm, respectively, and the addition of PEOZ-CHMC or PEG-DSPE had no influence on EE and particle size. The zeta potentials of three kinds of liposomes were negative. The release behavior of various DOX liposomes in vitro was investigated by dialysis method. In phosphate buffer solution (PBS) at pH 7.4, DOX x HCl was released from PEOZ-DOX-L in a sustained manner. While in PBS at pH 5.0, the release rate of DOX x HCl from PEOZ-DOX-L increased significantly, which suggested DOX x HCl was released from PEOZ-DOX-L in a pH-dependent manner. The intracellular delivery of liposomes was investigated by confocal laser scanning microscopy (CLSM). The CLSM images indicated that PEOZ-DOX-L showed efficient intracellular trafficking including endosomal escape and release DOX x HCl into nucleus, as well as the DOX-L and PEG-DOX-L had no this effect. The cytotoxicity of liposomes against MCF-7 cells was detected by using MTT assay. The results showed that antiproliferative effects of PEOZ-DOX-L enhanced with pH value decreased, whereas DOX-L and PEG-DOX-L did not have any significant difference in inhibitions at different pH conditions. Therefore, the problems of the inhibition of cellular uptake of liposomes and the failed endosomal escape of pH-sensitive liposomes by PEG chain can be overcome by the pH-sensitive liposomes constructed by PEOZ-CHMC.
Cell Nucleus ; Doxorubicin ; analogs & derivatives ; chemistry ; Endosomes ; Formates ; chemistry ; Humans ; Liposomes ; chemistry ; MCF-7 Cells ; Microscopy, Confocal ; Particle Size ; Phosphatidylethanolamines ; Polyamines ; chemistry ; Polyethylene Glycols ; chemistry

OBJECTIVETo approach the sequential release of antitumor drugs and promote the effect of chemotherapy.

METHODSAdriamycin (ADM) and carboplatin (CBP) were respectively microcapsulated with ethylcellulose by organic phase separation. The morphology and sizes of the microcapsules were observed and measured with light microscope and scanning electromicroscope. The contents and the release rates of ADM and CBP in microcapsules were measured with fluorescence spectrophotometer and high-efficiency phantom chromatic (HPC) spectrum respectively. The antitumor sensitivity test in vitro was devised with MTT assay.

RESULTSThe microcapsules of ADM and CBP were spherical in shape with diameters of 196 +/- 64 micro m and 214 +/- 48 micro m respectively. The contents of one-layer and two-layer CBP and ADM microcapsules were 51.4%, 35.7% and 39.8% respectively, with the release rates in vitro of 62.4%/day, 54.8%/day and 48.2%/8 h. The results of drug sensitivity test in vitro demonstrated that the current preparation has never affected the stability and antitumor activity of CBP and ADM.

CONCLUSIONMicrocapsules with different drugs and different thickness of material have different release rate. Combined arterial chemoembolization with different microcapsules could approach the sequential release and promote the effect of chemotherapy.

Antineoplastic Agents ; administration & dosage ; chemistry ; Carboplatin ; administration & dosage ; Cellulose ; administration & dosage ; analogs & derivatives ; Chemoembolization, Therapeutic ; Doxorubicin ; administration & dosage ; Drug Delivery Systems ; Humans ; Tumor Cells, Cultured

OBJECTIVETo explore the clinical efficacy and adverse effects of GHA(G-CSF+homoharringtonin+cytarabine C) and new combined priming chemotherapeutic regimens(GHAA/GHTA) with high efficacy and low toxicity for treatment of relapsed and refractory acute myeloid leukemia(AML) and myelodysplastic syndrome(MDS), and to analyze the relation of above-mentioned regimens with the expression of co-stimuolating molecule B7.1.

METHODSStandard GHA regimen consisting of G-CSF: 100 µg/(m2·d) subcutaneous injection, d 0-14; homoharringtonine: 1.0 mg/(m2·d) intravenous drip, d 1-14; Ara-C: 7.5-10 mg/(m2·d) subcutaneous injection, q12h, d 1-14. Other regimens as GHAA/GHTA were combined respectively with aclarubicin 20 mg d 1-7, or pirarubicin 20 mg d 1-7. 74 patients with refractory AML and 46 patients with MDS received these priming chemotherapy. The clinical efficacy and toxicity of above-mentioned priming chemotherapy were compared with 56 patients received routine chemotherapy (MA/TAE) respectively. And the expression of costimulatory molecule B7.1 on leukemia cells in patients of different subtypes was also detected by immunofluoressence and its relationship with clinical efficiency was explored.

RESULTS(1) for AML patients treated with priming chemotherapy, the total remission was 67.56% (CR 54.05%, PR 13.51%), which was much higher than that of patients received routine chemotherapy (P<0.05). The CR rate of AML-M2 and AML-M5 group (65.51%, 61.90% respectively) was much higher than that of AML other subtypes (P<0.05), and the longest remission period lasted for 4 years; (2) for MDS patients treated with priming chemotherapy, the total remission was 60.87% (CR 45.65%, PR 15.22%), which was also significantly higher than that of patients received routine chemotherapy (P<0.05); (3) in comparison with patients received standard GHA priming regimen, the remission rate of combined priming chemotherapy GHAA/GHTA was significantly higher both in patients with AML (85.18%) and MDS (81.25%); (4) side effects after chemotheropy, including granulocyte deficiency, thrombocytopenia and anemia etc, lasted for 7-14 days; the severe infection rate was 1%, there were no severe bleeding, digest effect and damage of function in heart, liver and kidney. The therapy-related mortality was zero. Compared with routine chemotherapy, priming chemotherapy proved significantly safe and effective (P<0.05); (5) the expression rate of costimulatory molecule B7.1 showed large variance between AML and MDS, it was higher in AML-M2/AML-M5 and lower in AML of other subtypes (P<0.05). In the same case, B7.1 expression was positive correlated with efficiency of priming chemotherapy.

CONCLUSIONGHA priming chemotherapy, as well as other combination regimens GHAA/GHTA, are well-tolerated, effective regimens for refractory AML and advanced MDS, without severe side effects and therapy-related mortality. Especially the new regimens GHAA/GHTA has better efficacy, which are proved more efficient than conventional GHA. Efficiency of priming chemotherapy is positive correlated with B7.1 expression, its mechanism will be further explored.

Aclarubicin ; analogs & derivatives ; Antineoplastic Combined Chemotherapy Protocols ; B7-1 Antigen ; Cohort Studies ; Cytarabine ; Doxorubicin ; analogs & derivatives ; Granulocyte Colony-Stimulating Factor ; Granulocytes ; Harringtonines ; Humans ; Leukemia, Myeloid, Acute ; Myelodysplastic Syndromes ; Recurrence ; Thrombocytopenia

This study was aimed to compare the efficacy and adverse effects of PD (bortezomib + dexamethasone) and VAD (vincristine + adriamycin + dexamethasone) as regimens for treatment of multiple myeloma patients. 21 and 31 multiple myeloma patients were enrolled in the PD and VAD groups respectively which received 2 to 5 courses of treatments, and both clinical effects and adverse reactions were observed. In the all 52 patients, 48 were newly diagnosed and the other 4 patients had accepted 1 to 2 courses of M2 or MP treatment, but didn't get PR. In 52 patients, 4, 4, 8 and 5 patients accepted 2, 3, 4 and 5 courses of PD regimen respectively, while 6, 11, 12 and 2 patients accepted 2, 3, 4 and 5 courses of VAD regimen respectively. The results indicated that the rate of good efficacy (both CR and VGPR) in PD group was 57.1%, while the rate of good efficacy in VAD group was 16.1%, there was significant difference (p = 0.0052). The percentage of patients who got CR, VGPR and PR in PD and VAD groups were 95.2% and 74.2% respectively, there was no significant difference (p = 0.1108). The incidences of adverse effects in 2 groups were similar, which included hematological toxicity, liver and kidney functional lesion, peripheral neuropathy, infection, interstitial pneumonia. It is concluded that compared with conventional VAD chemotherapy, PD may improve CR and VGPR rate in newly diagnosed patients with multiple myeloma, meanwhile it does not bring about more and worse toxicity.
Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; therapeutic use ; Bleomycin ; analogs & derivatives ; therapeutic use ; Dexamethasone ; therapeutic use ; Doxorubicin ; therapeutic use ; Female ; Humans ; Male ; Middle Aged ; Multiple Myeloma ; drug therapy ; Treatment Outcome ; Vincristine ; therapeutic use

OBJECTIVETo investigate the value of in vivo proton magnetic resonance spectroscopy (MRS) in the assessment of hepatocellular carcinoma (HCC) and monitor its metabolic change shortly after transcatheter arterial chemoembolization (TACE).

METHODSIn this prospective study, 28 consecutive patients with large HCC (> or = 3 cm in diameter) confirmed by fine needle aspiration biopsy were recruited. The 1H MRS of all hepatic lesions and some uninvolved liver parenchyma were performed with 1. 5T whole body MR scanner. Among them, 15 cases were evaluated again about one week after TACE. The main metabolites such as choline and lipid before and after interventional therapy were measured to assess the early response of the tumor.

RESULTSThe technical success rate of 1H MRS in liver was high (33/41, 80%), closely related to breath motion, location of lesion, and size of voxel. In spectra, the choline compound peak of HCC elevated compared with uninvolved liver parenchyma. After TACE, both the amplitude and the area of choline resonance peak significantly descended (choline-to-lipid ratios from 0.352 +/- 0.080 to 0.167 +/- 0.030, P = 0.026; from 0.205 +/- 0.060 to 0.070 +/-0.020, P = 0.042, respectively); yet lipid resonance peak ascended.

CONCLUSIONSIn vivo 1H MRS is technically feasible for the evaluation of large focal hepatic lesions, however, the reproducibility and stability are not as good as routine MR scan. 1H MRS can monitor the early stage metabolic changes of HCC after TACE but limitation like quantification still exists.

Adult ; Aged ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; Carcinoma, Hepatocellular ; diagnosis ; therapy ; Chemoembolization, Therapeutic ; Cisplatin ; administration & dosage ; Doxorubicin ; administration & dosage ; analogs & derivatives ; Female ; Humans ; Liver ; pathology ; Liver Neoplasms ; diagnosis ; therapy ; Magnetic Resonance Spectroscopy ; methods ; Male ; Middle Aged

Recently various peptide receptors which displayed the highest binding affinity and specificity with their peptide ligands by ligand-receptor have been exploited to develop drug delivery system which can directionally deliver drug to targeted cell. It is significant to study and applicate, including targeted drug delivery system mediated by bombesin receptor, somatostatin receptor, SynB3 receptor, LH-RH receptor and other peptide receptor, et al. Several small peptide fragments were selected as carriers radicals combining doxorubicin, 2-pyrrolino-DOX, methotrexate, cis-platinum, and camptothecin to form hybrid cytotoxic analogs. These highly potent cytotoxic analogs have been designed as targeted anti-tumor agents for the treatment and study of various cancers that possess receptors for the carrier peptide.
Animals ; Antineoplastic Agents ; therapeutic use ; Doxorubicin ; analogs & derivatives ; therapeutic use ; Drug Delivery Systems ; Humans ; Neoplasms ; drug therapy ; metabolism ; Oligopeptides ; metabolism ; Pyrroles ; therapeutic use ; Receptors, Bombesin ; metabolism ; Receptors, LHRH ; metabolism ; Receptors, Somatostatin ; metabolism

The aim of this study was to evaluate the effect of dimethyl amiloride (DMA), a specific inhibitor of Na(+)/H(+) exchanger-1 (NHE-1), on intracellular pH value (pHi), proliferation and apoptosis of HL-60/ADM cells in vitro. After treatment with DMA at different doses, pHi of HL-60 and HL-60/ADM cell lines were determined by using pH-sensitive fluorescence dye BECEF-AM; the rate of growth inhibition of cells was detected with MTT assay; cell cycle was detected by flow cytometric DNA analysis; cell apoptosis was observed with terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL). The results showed that pHi in HL-60/ADM cells was higher than that in HL-60 cells. After treatment with DMA at different doses, pHi decreased, the rate of growth inhibition and the rate of apoptotic cells in HL-60/ADM cells were all higher than those in HL-60 cells. Meanwhile, after treatment with DMA during 100 micromol/L to 150 micromol/L, the increase amplitude of G(0)/G(1) phase cells and the decrease amplitude of S + G(2)/M cells in HL-60/ADM cells were higher than those in HL-60 cells. It is concluded that by causing intracellular acidification, the NHE-1-specific inhibitor DMA inhibits proliferation of HL-60/ADM cells and induces apoptosis of HL-60/ADM cells, and the degree of this growth inhibition of HL-60/ADM cells is higher than that of HL-60 cells.
Amiloride ; analogs & derivatives ; pharmacology ; Apoptosis ; drug effects ; Cell Cycle ; drug effects ; Cell Proliferation ; drug effects ; Doxorubicin ; pharmacology ; Drug Resistance, Neoplasm ; HL-60 Cells ; Humans ; Hydrogen-Ion Concentration ; Sodium-Hydrogen Exchangers ; antagonists & inhibitors

This study was aimed to establish rat bladder tumor animal models to investigate the in viva antitumor effect of polyanhydride-pirarubicin (PAD-THP), a long-lasting anti-cancer implant, in the bladder tumor of animal models. The model of bladder cancer was set up with N-butly-N-(4 hydroxybutyl) nitrosamine (BBN) feeding into rats. The PAD-THP long-acting anti-cancer implants containing the drugs and the same dose of the THP naked drug were placed under the bladder mucosa of bladder tumor model in vivo. The pirarubicin plasma concentration was measured with high performance liquid chromatography (HPLC) detection in vivo. The effective drug concentration and lasting period were observed and compared in the animal bodies. The tumor sizes were measured before and after the treatment. The in viva antitumor effects were analyzed and compared. The results showed that more significant antitumor effect of PAD-THP implants on the local drug release characteristics were presented compared with that of the same dose of THP bare drug group and there were significant differences (P<0. 05) between the two methods. All the results indicated that the PAD-THP anti-cancer implants in the postoperative local treatment of bladder tumors would show prosperous in the future for clinical application.
Animals ; Antineoplastic Agents ; administration & dosage ; Butylhydroxybutylnitrosamine ; Delayed-Action Preparations ; administration & dosage ; Disease Models, Animal ; Doxorubicin ; administration & dosage ; analogs & derivatives ; Female ; Implants, Experimental ; Polyanhydrides ; administration & dosage ; Rats ; Rats, Sprague-Dawley ; Urinary Bladder Neoplasms ; chemically induced ; drug therapy ; pathology

OBJECTIVETo compare the efficacy and toxicity of the chemotherapeutic regimen containing pirarubicin and mitoxantrone on the treatment of relapsed or refractory acute myeloid leukemia (AML) in adults.

METHODSIn this open prospective multicentre study, we randomly assigned patients with relapsed or refractory AML to receive TAE regimen (pirarubicin+cytarabine+etoposide) versus MAE regimen (mitoxantrone + cytarabine + etoposide). The efficacy and toxicity were compared between the two groups.

RESULTS56 patients entered this clinical trial. The complete remission (CR) rate on TAE arm was 79.0% versus 55.6% on MAE arm with the overall response (OR) rates of 86.8% versus 88.9%, respectively. The CR was higher on TAE arm (P=0.035) but with no significant difference between the two groups regarding the overall response (OR) rate. The regimens were well tolerated in both groups. Hematologic and non-hematologic toxicity were similar except relatively lower the mean dosage of G-CSF, red blood cells and platelets transfusion on TAE arm. No significant differences were seen between the two groups regarding the overall survival and relapse free survival rates.

CONCLUSIONTAE regimen might be an effective salvage therapy in patients with relapsed or refractory AML.

Adult ; Antineoplastic Combined Chemotherapy Protocols ; administration & dosage ; therapeutic use ; Dactinomycin ; administration & dosage ; Doxorubicin ; administration & dosage ; analogs & derivatives ; Etoposide ; administration & dosage ; Granulocyte Colony-Stimulating Factor ; administration & dosage ; Humans ; Leukemia, Myeloid, Acute ; drug therapy ; Methotrexate ; administration & dosage ; Prospective Studies ; Recurrence ; Remission Induction

OBJECTIVETo investigate the in vitro effect of bortezomib (BTZ) alone and in combination with pirarubicin (THP) on the growth inhibition of human cutaneous T-cell lymphoma cell line Hut-78.

METHODSHut-78 cells were cultured with different concentrations of BTZ or THP alone and the two drugs combination for 48 h. Cell proliferation, cell cycle and apoptosis were evaluated. The cell cycle inhibitor P21 was determined by Western blot.

RESULTSBTZ or THP alone significantly inhibited the growth of Hut-78 cells in a time- and dose-dependent manner. In the combination groups, the inhibitory effect of BTZ followed by THP was the highest (P < 0.01). When the inhibition rate was more than 50%, the combination index analysis showed significant synergistic if treated with BTZ followed by THP or the two at the same time, but antagonistic if treated with THP followed by BTZ. With the inhibition rate increasing, only the synergistic effect of BTZ followed by THP was further increased. The apoptosis rate of BTZ followed by THP was higher than that of single agent each (P < 0.01). BTZ alone significantly increased the proportion of cells in G(2)/M phase (P < 0.01) in a dose-dependent manner and up-regulated the expression level of P21. Sequential THP notably enhanced BTZ-induced cell cycle arrest and apoptosis.

CONCLUSIONSBTZ alone effectively induces growth inhibition and apoptosis of Hut-78 cells in vitro. BTZ followed by THP can synergistically enhance this cytotoxic effect. The mechanism may be that THP enhances BTZ-induced G(2)/M arrest and P21 up-regulation.

Antineoplastic Agents ; pharmacology ; Apoptosis ; drug effects ; Boronic Acids ; pharmacology ; Bortezomib ; Cell Line, Tumor ; drug effects ; Cell Proliferation ; drug effects ; Doxorubicin ; analogs & derivatives ; pharmacology ; Drug Synergism ; Humans ; Lymphoma, T-Cell ; pathology ; Pyrazines ; pharmacology