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Journal of Experimental Therapeutics &... Jul 2004Toxicity is a major deterrent to achieving substantial improvements in cancer management, since most anticancer drugs inadequately distinguish normal and neoplastic...
Toxicity is a major deterrent to achieving substantial improvements in cancer management, since most anticancer drugs inadequately distinguish normal and neoplastic tissues. Improving the differential between beneficial and toxic effects of therapy--therapeutic index--is a major clinical objective, but therapeutic index for cytotoxic drugs is narrow. Fresh tumor and normal cells from 59 patients with acute myeloid leukemia, non-Hodgkin's lymphoma, ovarian cancer and cancers of unknown origin were tested for ex vivo drug sensitivity using apoptosis by morphology assays. Drugs tested included carboplatin, doxorubicin, vincristine, cytarabine, fludarabine, mafosfamide and etoposide. Therapeutic index was derived from the ratio of normal and tumor cell LC90s. Individual patient therapeutic index varied markedly for different drugs and drug therapeutic index varied from patient to patient ranging from extremely unfavourable (<0.001) through excellent (>1000) reflecting patient heterogeneity. Therapeutic index for each drug was consistent with clinical expectations. Significantly, there was no relationship between normal and tumor cell LC90s. We conclude that further laboratory and clinical evaluation is required but the derived ex vivo therapeutic index could enhance choice of chemotherapy by reducing toxicity and/or improving efficacy.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Apoptosis; Cells, Cultured; Child; Child, Preschool; Drug Screening Assays, Antitumor; Humans; Middle Aged; Neoplasms; Tumor Cells, Cultured
PubMed: 15500009
DOI: No ID Found -
Oncogene Nov 2004Mantle cell lymphoma (MCL) is a mature B-cell proliferation characterized by the presence of translocation t(11;14)(q13;q32), an aggressive clinical course, and poor...
Mantle cell lymphoma (MCL) is a mature B-cell proliferation characterized by the presence of translocation t(11;14)(q13;q32), an aggressive clinical course, and poor response to chemotherapy. The majority of drugs currently used in the treatment of lymphoproliferative disorders induce cell death by triggering apoptosis, but few data concerning drug-induced apoptosis in MCL have been reported. We have analysed the mechanisms of drug-induced cell death in four cell lines with the t(11;14) and in primary cells from 10 patients with MCL. Mitoxantrone, a topoisomerase II inhibitor, induced a strong cytotoxic effect in three cell lines (JVM-2, REC-1, and Granta 519), and in primary MCL cells. This cytotoxic effect due to apoptosis induction was observed despite the presence of either p53 or ATM abnormalities. However, no cytotoxic effect was detected after incubation with DNA-damaging agents in the NCEB-1 cell line, carrying p53 and ATM alterations, despite the presence of functional mitochondrial machinery. These results support that mitoxantrone can be effective in the treatment of MCL but that this activity requires the integrity of functional DNA-damage response genes.
Topics: Annexin A5; Antineoplastic Agents; Apoptosis; Cell Cycle; Cell Death; Cell Line, Tumor; Cell Survival; Coloring Agents; Cyclophosphamide; DNA Damage; Enzyme Inhibitors; Flow Cytometry; Genes, p53; Humans; In Situ Hybridization, Fluorescence; Leukocytes, Mononuclear; Lymphoma, Mantle-Cell; Membrane Potentials; Mitochondria; Mitoxantrone; Proteins; Reactive Oxygen Species; Staurosporine; Time Factors; Translocation, Genetic; Tumor Suppressor Protein p53; Vidarabine
PubMed: 15480431
DOI: 10.1038/sj.onc.1208084 -
Life Sciences Jul 20042-Methoxyestradiol (2ME) is an endogenous estradiol metabolite, which acts antiproliferative in various tumor cell lines independent of the hormone receptor status. We...
2-Methoxyestradiol (2ME) is an endogenous estradiol metabolite, which acts antiproliferative in various tumor cell lines independent of the hormone receptor status. We investigated whether combinations of 2ME with various chemotherapeutic or endocrine compounds may result in an additive effect on the proliferation of human breast cancer cells. The breast cancer cell lines MCF-7 (receptor-positive), BM (receptor-negative) and a MCF-7 line transfected with the aromatase gene were used. All cell lines were incubated in the concentration range of 0.8 microM to 25 microM with 2ME alone and in equimolar combinations with the following compounds: epirubicine, daunorubicine, paclitaxel, docetaxel, carboplatin, vinorelbine, 5-fluorouracil, mafosfamide and 4-OH tamoxifen. The effect of letrozole and 2ME alone and in equimolar combinations was tested in the concentration range of 0.6 to 1 microM. Proliferation was measured after 4 days using the ATP-chemosensitivity test. In MCF-7 cells 2ME in combination with 4OH-tamoxifen, epirubicine, docetaxel, 5-fluoprouracil, mafosfamide and carboplatin led to an additive effect. In BM cells only 2ME combined with 4OH-tamoxifen, daunorubicine and mafosfamide showed an additive action. Both letrozole and 2ME were nearly similar effective in inhibition of the aromatase gene. Here no additive effect was found. 2ME displayed antiproliferative actions in various human breast cancer cells. In addition 2ME was able to increase the antiproliferative property of certain antihormones and cytostatic substances. Furthermore 2ME exhibits a similar property as compared to letrozole in inhibiting the aromatase activity. Since 2ME was well tolerated in a recently conducted phase II trial in patients with refractory metastatic breast cancer, the combination of 2ME with chemotherapeutics or antihormones may offer a new clinically relevant treatment regimen.
Topics: 2-Methoxyestradiol; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Cell Division; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Synergism; Estradiol; Female; Humans
PubMed: 15219808
DOI: 10.1016/j.lfs.2004.02.023 -
Methods and Findings in Experimental... Mar 2004Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from...
Gateways to Clinical Trials is a guide to the most recent clinical trials in current literature and congresses. The data in the following tables has been retrieved from the Clinical Studies Knowledge Area of Prous Science Integrity(R), the drug discovery and development portal, http://integrity.prous.com. This issue focuses on the following selection of drugs: Activated protein C concentrate, Ad-CD154, Adeno-Interferon gamma, alemtuzumab, APC-8024, 9-aminocamptothecin, aprepitant, l-arginine hydrochloride, aripiprazole, arsenic trioxide, asimadoline; O6-Benzylguanine, bevacizumab, Bi-20, binodenoson, biphasic insulin aspart, bivatuzumab, 186Re-bivatuzumab, BMS-181176, bosentan, botulinum toxin type B, BQ-123, bryostatin 1; Carboxy- amidotriazole, caspofungin acetate, CB-1954, CC-4047, CDP-860, cerivastatin sodium, clevidipine, CTL-102; 3,4-DAP, darbepoetin alfa, decitabine, desloratadine, DHA-paclitaxel, duloxetine hydrochloride; Efalizumab, EGF vaccine, eletriptan, eniluracil, ENMD-0997, eplerenone, eplivanserin, erlosamide, ertapenem sodium, escitalopram oxalate, esomeprazole magnesium, eszopiclone, everolimus, exatecan mesilate, exenatide, ezetimibe; Fondaparinux sodium, FR-901228, FTY-720; Gefitinib, gemtuzumab ozogamicin, gepirone hydrochloride; Hexyl insulin M2, human insulin; Imatinib mesylate, insulin detemir, insulin glargine, iodine (I131) tositumomab, ISV-205, ivabradine hydrochloride, ixabepilone; Levetiracetam, levocetirizine, linezolid, liposomal NDDP, lonafarnib, lopinavir, LY-156735; Mafosfamide cyclohexylamine salt, magnesium sulfate, maxacalcitol, meclinertant, melagatran, melatonin, MENT, mepolizumab, micafungin sodium, midostaurin, motexafin gadolinium; Nesiritide, NS-1209, NSC-601316, NSC-683864; Osanetant; Palonosetron hydrochloride, parecoxib sodium, pegaptanib sodium, peginterferon alfa-2a, peginterferon alfa-2b, pegylated OB protein, pemetrexed disodium, perillyl alcohol, picoplatin, pimecrolimus, pixantrone maleate, plevitrexed, polyglutamate paclitaxel, posurdex, pramlintide acetate, prasterone, pregabalin; Rasburicase, rimonabant hydrochloride, rostaporfin, rosuvastatin calcium; SDZ-SID-791, sibrotuzumab, sorafenib, SU-11248; Tadalafil, targinine, tegaserod maleate, telithromycin, TheraCIM, tigecycline, tiotropium bromide, tipifarnib, tirapazamine, treprostinil sodium; Valdecoxib, Valganciclovir hydrochloride, Vardenafil hydrochloride hydrate; Ximelagatran; Zofenopril calcium, Zoledronic acid monohydrate.
Topics: Clinical Trials as Topic; Humans
PubMed: 15071612
DOI: No ID Found -
Cancer Genomics & Proteomics 2004The purpose of this investigation was to evaluate whether different protein patterns exist between drug-sensitive and drug-resistant kidney carcinomas. As a first step,...
The purpose of this investigation was to evaluate whether different protein patterns exist between drug-sensitive and drug-resistant kidney carcinomas. As a first step, expressions of drug resistance proteins (P-glycoprotein (P-gp), glutathione S-transferase-σ (GST-σ), DNA topoisomerase IIα (Topo IIα), alkaline phosphatase (AP), catalase, thymidylate synthetase, metallothionein), signal transducers (protein kinase Cα/β (PKCα/β)), proliferation-associated proteins (Ki-67) and proteins of proto-oncogenes and tumor suppressors (ErbB1, ErbB2, Fos, Jun, Myc, Ras and p53) of primary cell cultures of human kidney carcinomas of 18 patients were determined. The expression levels of the proteins were compared with the response to doxorubicin, vincristine or mafosfamide measured by growth inhibition and nucleotide incorporation assays. As a second step, those proteins showing a relationship to doxorubicin resistance (P-gp, GST-σ, Topo IIα, PKCα/β, AP, ErbB1, ErbB2, Fos, K-Ras, p53, and Ki-67) were analyzed by hierarchical cluster analysis and clustered image mapping. The resulting clusters were correlated with the drug resistance data. The data shows that different protein expression profiles exist between drug-resistant and -sensitive kidney carcinoma cell cultures. Finally, the clustered image map (CIM) demonstrates a sensitive area that is characterized by a lower expression of proteins and a resistant area with a higher expression of proteins. These results may have important implications for the diagnosis and therapy of kidney cancer. The resistance proteins and the resistance-related factors found in the present analysis may be suitable parameters to predict treatment outcome of kidney cancer.
PubMed: 31394613
DOI: No ID Found -
Journal of Neuro-oncology Sep 2003Treatment options for leptomeningeal disseminated brain tumors are limited by the lack of effective drugs for intrathecal therapy of non-hematologic malignancies. We... (Clinical Trial)
Clinical Trial
Treatment options for leptomeningeal disseminated brain tumors are limited by the lack of effective drugs for intrathecal therapy of non-hematologic malignancies. We report on our experience with an intraventricular therapy consisting of mafosfamide, a preactivated cyclophosphamide derivative, and etoposide. Between May 1994 and 2002, 26 patients aged 2-19 years with various intensely pretreated disseminated brain tumors received intraventricular mafosfamide via an indwelling subcutaneous reservoir. Twenty-three of them received a dose of 20 mg. Mafosfamide was administered once or twice weekly until remission was achieved and every 2-6 weeks thereafter as maintenance therapy for a total of 736 administrations (2-63/patient). Since March 1998, two patients were switched to receive intraventricular etoposide and nine received etoposide alternating with mafosfamide. Etoposide was given at a dose of 0.5 mg x 5 d every 3-6 weeks for a total of 122 courses (1-29/patient). Immediate toxicities such as transient headaches, nausea, and vomiting occurred with mafosfamide but were manageable with premedication. Etoposide did not cause any discomfort. No long-term toxicities attributable to intrathecal therapy as evidenced by magnetic resonance imaging or neurologic evaluation were observed. Since all patients received some sort of concurrent anti-cancer therapy, the efficacy of intrathecal therapy cannot be assessed independently. However, seven of 13 patients evaluable for response by cerebrospinal fluid (CSF) cytology developed CSF dissemination under systemic chemotherapy and cleared their CSF only after administration of intrathecal mafosfamide. In conclusion, intraventricularly administered mafosfamide at a dose of 20 mg and etoposide at a dose of 0.5 mg x 5 d for patients over 2 years of age are feasible and safe and may produce responses.
Topics: Adolescent; Adult; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Brain Neoplasms; Child; Child, Preschool; Cyclophosphamide; Etoposide; Feasibility Studies; Female; Follow-Up Studies; Headache; Humans; Injections, Intraventricular; Injections, Spinal; Male; Meningeal Neoplasms; Nausea; Pain; Treatment Outcome
PubMed: 14558599
DOI: 10.1023/a:1025633704071 -
Anticancer Research 2003The low cellular yield of a breast cancer sample represents a limiting factor for in vitro chemosensitivity/chemoresistance testing. The use of in vitro serially...
UNLABELLED
The low cellular yield of a breast cancer sample represents a limiting factor for in vitro chemosensitivity/chemoresistance testing. The use of in vitro serially cultured cells can help overcome this obstacle.
MATERIALS AND METHODS
In vitro drug resistance of cells cultured from mammary carcinomas by the 3T3 feeder-layer technique was tested by the MTT assay. Out of the 33 tested cultures, 9 were derived from cells obtained from true-cut biopsies of primary tumours, with sample volume less than 0.03 cm3. The cultures were treated with 6 anticancer drugs at 6-8 concentrations. The chemoresistance of cultured cells was monitored by the surviving cell fraction as a function of the drug concentration.
RESULTS
The average time to obtain a result was 28 days. The volume of an original sample had no effect on the in vitro resistance of a culture, suggesting minimal alteration of in vitro chemosensitivity of cells by their cultivation. Histopathological grade, estrogen receptor status or expression of the c-erb-B2 protein of the original tumours did not significantly correlate with the resistance of cultures. Individual drugs displayed distinct in vitro effectiveness. Paclitaxel and cisplatin were the most potent drugs. Gemcitabine, vinorelbine and mafosfamide were the least potent drugs. Doxorubicin and gemcitabine most frequently failed to completely metabolically inhibit 100% of cultured cells at any concentration.
CONCLUSION
Combination of the optimised feeder-layer cultivation technique and the MTT test permits extensive drug resistance testing from very small breast cancer samples.
Topics: 3T3 Cells; Animals; Antineoplastic Agents; Biopsy; Breast Neoplasms; Cell Survival; Drug Resistance, Neoplasm; Drug Screening Assays, Antitumor; Feasibility Studies; Humans; Mice; Receptor, ErbB-2; Receptors, Estrogen; Tetrazolium Salts; Thiazoles; Tumor Cells, Cultured
PubMed: 12894546
DOI: No ID Found -
American Journal of Hematology Apr 2003Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by hereditary missense mutations of the mitochondrial genome. Primary...
Leber's hereditary optic neuropathy (LHON) is a bilateral subacute optic neuropathy caused by hereditary missense mutations of the mitochondrial genome. Primary mutations are located at nucleotide positions 11778, 3460, and 14484 in genes encoding subunits of complex I of the respiratory chain. It has been suggested that degenerative changes in the optic nerve might be mediated by apoptosis. Therefore, we hypothesized that patients affected with LHON might show altered sensitivity to cytotoxic drugs. Here we report the case of a LHON patient carrying the 11778 mutation who required chemotherapy for malignant lymphoma. Using in vitro assays, we found that the patient's peripheral blood mononuclear cells did not show altered vulnerability to cytotoxic drugs. The patient was treated with combination chemotherapy and consolidating radiotherapy, leading to complete remission without inappropriately severe acute or chronic side effects. These data indicate that the 11778 mutation does not change cellular response to cytotoxic drugs in a clinically apparent manner.
Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Cells, Cultured; Combined Modality Therapy; Cyclophosphamide; DNA, Mitochondrial; Drug Resistance, Neoplasm; Epirubicin; Female; Humans; Leukocytes, Mononuclear; Lymphoma, Non-Hodgkin; Male; Optic Atrophy, Hereditary, Leber; Prednisone; Remission Induction; Vincristine
PubMed: 12666138
DOI: 10.1002/ajh.10301 -
Journal of Hematotherapy & Stem Cell... Feb 2003Sublethal cyclophosphamide treatment induces unique regeneration patterns in bone marrow and the spleen of a mouse. Colony-forming units spleen (CFU-S)(day 8),...
Sublethal cyclophosphamide treatment induces unique regeneration patterns in bone marrow and the spleen of a mouse. Colony-forming units spleen (CFU-S)(day 8), CFU-granulocyte-macrophage (GM), nucleated cell counts, and their differentials in bone marrow, spleen, and peripheral blood were determined in mice treated with a single dose of cyclophosphamide. To study further the mechanisms underlying the unique patterns of hematopoietic regeneration after cyclophosphamide, mRNA levels for stem cell factor (SCF), Flt-3 ligand, and macrophage inflammatory factor (MIP)-1 alpha cytokines were determined in bone marrow and spleen. Granulocyte precursor cells were less depleted by cyclophosphamide compared to erythroid nucleated cells and lymphocytes both in bone marrow and spleen. Rapid expansion of granulopoietic cells increased the granulocytic/erythroid ratio significantly during regeneration. CFU-S in the bone marrow and the spleen showed different sensitivity in vivo but not in vitro to cyclophosphamide; CFU-GM were equisensitive in both sites. In bone marrow, an initial fast recovery of CFU-S and CFU-GM on days 2 to 3 was followed by a secondary deep decline in their numbers occurring between days 5 and 7. This decline was accompanied with a depression of CFU-S proliferation and with significantly increased CFU-S numbers in the peripheral blood. In the spleen, absolute CFU-S and CFU-GM numbers were increased several-fold at this time. Seven days after cyclophosphamide, the spleen contained 69% of the total body CFU-S compared to 4% in controls. Splenectomy did not abolish the secondary disease of CFU-S in the bone marrow, but it led to a marked elevation of circulating leukocytes and CFU-S. There was an eight-fold increase in the SCF mRNA level in the bone marrow 2 days after cyclophosphamide, corresponding with a high proliferation rate of CFU-S. No significant changes in mRNAs for Flt-3 ligand and MIP-1 alpha have been found. This in-depth analysis of murine hematopoietic responses to cyclophosphamide provides evidence for the complexity of the involved local and systemic regulations. This represents a significant challenge to experimental hematology, which could now be tackled with methods allowing the study of changes in the gene expression during cyclophosphamide-induced hematopoietic damage.
Topics: Aldehyde Dehydrogenase; Animals; Bone Marrow Cells; Cell Differentiation; Cell Division; Cell Nucleus; Chemokine CCL4; Cyclophosphamide; Cytokines; DNA, Complementary; Dose-Response Relationship, Drug; Hematopoiesis; Hematopoietic Stem Cells; Immunosuppressive Agents; Lymphocytes; Macrophage Inflammatory Proteins; Male; Membrane Proteins; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Protein Synthesis Inhibitors; RNA, Messenger; Spleen; Stem Cells; Thymidine; Time Factors
PubMed: 12662436
DOI: 10.1089/152581603321210136 -
Haematologica Mar 2003Although chemotherapy in childhood acute myeloid leukemia (AML) has improved in the last decade, except for a group of better-risk patients (approximately one third),... (Clinical Trial)
Clinical Trial Comparative Study
BACKGROUND AND OBJECTIVES
Although chemotherapy in childhood acute myeloid leukemia (AML) has improved in the last decade, except for a group of better-risk patients (approximately one third), more than half the other patients relapse. The main objective of this study was to evaluate the results obtained with bone marrow transplants, either allogeneic (allo-BMT) or autologous (auto-BMT), following two intensive consolidation courses in a series of children with high-risk (HR) AML according to morphologic and early-response BFM criteria. A second objective was to compare the results of auto-BMT with those of allo-BMT.
DESIGN AND METHODS
From April 1988 to May 2001, 79 children (< 15 years old) with de novo AML entered the prospective AML-88 trial in a single institution: 50 (63%) were qualified as having high-risk disease and are the subject of this study. After 1 or 2 induction courses, depending on early response, and two consolidations, patients with an HLA-identical sibling received an allo-BMT and all the others an auto-BMT. The conditioning regimen was cyclophosphamide and total body irradiation (TBI) in children over 3 years old and busulfan and etoposide in younger children. Bone marrow was purged with mafosfamide in auto-BMT and cyclosporine alone was given as graft-versus-host disease (GVHD) prophylaxis in allo-BMT.
RESULTS
At the end of the chemotherapy phase (induction and consolidation ), 46 of the 50 HR patients (92%) had attained complete remission (CR) after one (n=29), two (n=11) or three (n=6) courses; 2 more were in partial remission (PR) and 2 had died. The 48 patients in CR or PR received either an allo-BMT (17) or an auto-BMT (31). Hematologic reconstitution was significantly slower in auto-BMT recipients. Forty-one percent of patients who received allo-BMT suffered acute GVHD grades II-IV. Toxic deaths and relapse rates were 5.9% and 17.6%, respectively, in allo-BMT and 3.2% and 25.8%, respectively, in auto-BMT. Post-transplant 8-year event-free survival (EFS) was 74.5% (54-96) in allo-BMT and 74.2% (59-89) in auto-BMT. EFS and OS in all the series (50 patients) were 71% (59-83) and 73% (61-85), respectively, with a median follow-up of 7.2 years.
INTERPRETATION AND CONCLUSIONS
This study indicates that improved results in children with HR-AML can be obtained by either allo- or auto-BMT performed after two courses of intensive consolidation therapy provided good supportive therapy is given and reduced transplant -related mortality (TRM) is minimized.
Topics: Acute Disease; Adolescent; Antineoplastic Agents; Bone Marrow Transplantation; Child; Child, Preschool; Female; Humans; Infant; Leukemia, Myeloid; Male; Quality of Life; Risk; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome
PubMed: 12651268
DOI: No ID Found