1.Advances in the research of pharmacogenomics of cyclophosphamide.
Ling-Yan CHEN ; Xue-Ding WANG ; Min HUANG
Acta Pharmaceutica Sinica 2014;49(7):971-976
Cyclophosphamide (CPA) is the most common alkylating antineoplastic agent, as well as a strong immunosuppressant that is frequently applied to autoimmune diseases and organ transplantation. It is metabolized by cytochrome P450 oxidases (CYPs) to its active metabolite which played a critical role in therapy. CPA has serious and even fatal side effects, and its efficacy and adverse reactions are significantly varied among individuals. In this review, the association of the genetic polymorphisms in the metabolic enzymes and transporters involved in the disposition of CPA with the efficacy and adverse effects of CPA were summarized, thereby providing fundamental reference for further pharmacogenomic study of CPA.
Antineoplastic Agents, Alkylating
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pharmacology
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Cyclophosphamide
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pharmacology
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Humans
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NADPH-Ferrihemoprotein Reductase
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metabolism
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Pharmacogenetics
2.Progress in the studies on antitumor natural product ecteinascidin-743.
Ye WANG ; Zhan-zhu LIU ; Shi-zhi CHEN ; Xiao-tian LIANG
Acta Academiae Medicinae Sinicae 2004;26(4):474-478
The alkaloid ecteinascidin-743, isolated from the marine tunicate Ecteinascidia turbinata, binds to DNA and induces cytotoxic effects in several tumors. The drug is being codeveloped by Pharma Mar and Ortho Biotech. In May 2001 and October 2003, it was granted orphan drug status by the European Commission for soft tissue sarcoma and ovarian cancer, respectively. This paper reviews its research progress, including chemical synthesis, in vitro studies and mechanism of action, antitumor activity in vivo, toxicity, pharmacokinetics, and clinical studies.
Animals
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Antineoplastic Agents, Alkylating
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pharmacokinetics
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pharmacology
;
toxicity
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Dioxoles
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pharmacokinetics
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pharmacology
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toxicity
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Humans
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Isoquinolines
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pharmacokinetics
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pharmacology
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toxicity
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Tetrahydroisoquinolines
3.Effects of triptolide on proliferation and apoptosis of Jurkat cell line in acute T lymphocytic leukemia.
Gen-Hong YAO ; Jian-Feng LUAN ; Dong YE ; Jing-Mei YAN ; Qian-Hong LEI ; Pei-Yuan ZHU ; Jie JIN
Journal of Experimental Hematology 2008;16(3):506-509
The aim of this study was to investigate the anti-proliferation and pro-apoptosis of triptolide on Jurkat cell line in acute T lymphocytic leukemia. The Jurkat cells were treated with various concentrations of triptolide (0, 1, 2, 4, 8, 16 microg/L) for 12 hours. The inhibitory ratio was measured by Cell Counting Kit-8 assay. The effects of triptolide on apoptosis of Jurkat cells were determined by DNA fragmentation (DNA ladder), Hoechst 33258, PI and Annexin V-FITC/PI double staining. The results demonstrated that triptolide inhibited the proliferation of Jurket cells. The 50% inhibitory concentration (IC(50)) was 4.0 microg/L. Chromatin condensation in the cells treated with triptolide could be seen by light microscopy. DNA electrophoresis showed evidence of nuclear fragmentation (DNA ladder). The hypoploid (sub-G(1)) population was increased after treatment with triptolide. The translocation of phosphatidylserine at the outer surface of the cell plasma membrane could be induced by triptolide. After treatment with triptolide for 12 hours, the rates of apoptotic cells were significantly increased. Moreover, these pro-apoptosis effects were in time-dependent manner. It is concluded that triptolide can inhibit the proliferation and induce the apoptosis of Jurkat cells. This study provides experimental basis for clinical use of triptolide in leukemia therapy.
Antineoplastic Agents, Alkylating
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pharmacology
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Apoptosis
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drug effects
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Cell Proliferation
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drug effects
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Diterpenes
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pharmacology
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Epoxy Compounds
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pharmacology
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Humans
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Jurkat Cells
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Phenanthrenes
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pharmacology
4.Mechanism of thalidomide to enhance cytotoxicity of temozolomide in U251-MG glioma cells in vitro.
Song GAO ; Xue-jun YANG ; Wen-gao ZHANG ; Yan-wei JI ; Qiang PAN
Chinese Medical Journal 2009;122(11):1260-1266
BACKGROUNDGlioma is the most common primary brain tumor with poor prognosis. Temozolomide has been used with thalidomide to treat gliomas. We investigated the synergistic mechanism of these two drugs in vitro.
METHODSHuman malignant glioma cells U251-MG were cultured and assigned to four groups with different treatments for 3 days: temozolomide group (100 micromol/L), thalidomide group (100 microg/L), temozolomide (100 micromol/L) plus thalidomide group (100 microg/L) and control group. MTT assay was applied to evaluate the cell viability. Cell cycle was analyzed by flow cytometry. The ultra-structural features of autophagosomes were observed with electron microscope. Acridine orange and monodansylcadaverine were adopted to label autophagosomes and flow cytometry was applied for quantification of autophagosomes. The expression of autophagy-associated protein was detected by Western blotting.
RESULTSProliferation of tumor cell was obviously suppressed by temozolomide with thalidomide treatment than by either drug used alone (P = 0.000 for each day). The combination treatment induced cell cycle arrest at G0/G1 phase. Typical autophagic ultra-structural character was found after the combined treatment. Thalidomide promoted the autophagy induced by temozolomide. The autophagy-associated proteins-microtubule associated protein 1 light chain 3 (MAP1LC3) and Beclin1 were more significantly up-regulated by the combined treatment than temozolomide used alone (MAP1LC3, P = 0.000; Beclin1, P = 0.004). The expression level of phosphatase and tensin homolog deleted on chromosome ten (PTEN), which promoted autophagy by suppressing PI3K/Akt/mTOR signaling pathway, was elevated by thalidomide (thalidomide group: P = 0.000; combined group: P = 0.002).
CONCLUSIONSThalidomide enhances the cytotoxicity of temozolomide by promoting the autophagy induced by temozolomide. Contributing to the up-regulation of PTEN by thalidomide, the expression of autophagy associated protein-MAP1LC3 and Beclin1 was enhanced, which leads to a reinforced autophagy in the combined treatment of temozolomide and thalidomide in vitro.
Antineoplastic Agents, Alkylating ; pharmacology ; Autophagy ; drug effects ; Cell Line, Tumor ; Cell Proliferation ; drug effects ; Dacarbazine ; analogs & derivatives ; pharmacology ; Glioma ; pathology ; Humans ; Thalidomide ; pharmacology
5.Progress in research on triptolide.
Ming-xing LIU ; Jing DONG ; Ya-jiang YANG ; Xiang-liang YANG ; Hui-bi XU
China Journal of Chinese Materia Medica 2005;30(3):170-174
To further understand triptolide, this paper has introduced the pharmacology, pharmacokinetics, toxicity, the clinic application and semi-synthesis of triptolide on basis of importance and significant contents of reference which have been consulted in the past twenty years. Presently triptolide and Tripterygium wilfordii have been a hot spot of modernization of Chinese traditional medicine. It is very important to develop a new dosage form of high effect and low toxicity by making use of advanced technology according to its characteristics.
Animals
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Anti-Inflammatory Agents, Non-Steroidal
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pharmacology
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Antineoplastic Agents, Alkylating
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pharmacology
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Antispermatogenic Agents
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pharmacology
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Diterpenes
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chemical synthesis
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isolation & purification
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pharmacology
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toxicity
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Epoxy Compounds
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Humans
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Immunosuppressive Agents
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pharmacology
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Phenanthrenes
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isolation & purification
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pharmacology
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toxicity
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Tripterygium
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chemistry
6.Establishment of a mouse model bearing orthotopic temozolomide-resistant glioma.
Linyong SHI ; Hong LI ; Junwei GU ; Chong SONG ; Junjie LI ; Lei CHEN ; Qiang ZHOU ; Songtao QI ; Yuntao LU
Journal of Southern Medical University 2021;41(1):69-74
OBJECTIVE:
To establish a mouse model bearing orthotopic temozolomide (TMZ)-resistant glioma that mimics the development of drug resistance in gliomas
METHODS:
Seventy-eight adult C57BL/6 mice were randomly divided into 6 groups (
RESULTS:
The mouse models bearing TMZresistant glioma was successfully established. The cells from the high-dose induced group showed a significantly higher colony-forming rate than those from the high-dose control group (
CONCLUSIONS
Progressive increase of TMZ doses in mice bearing orthotopic gliomas can effectively induce TMZ resistance of the gliomas.
Animals
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Antineoplastic Agents, Alkylating/pharmacology*
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Brain Neoplasms/drug therapy*
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Cell Line, Tumor
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Disease Models, Animal
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Drug Resistance, Neoplasm
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Glioma/drug therapy*
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Mice
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Mice, Inbred C57BL
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Temozolomide/therapeutic use*
7.Suppression of nitric oxide on cytotoxicity of Lomustine in glioma cell line BT- 325.
Journal of Zhejiang University. Medical sciences 2003;32(6):519-528
OBJECTIVETo investigate the effect of nitric oxide (NO) on cytotoxicity of Lomustine (CCNU) in vitro.
METHODSCCNU was used to treat human glioma cell line BT-325 with different concentration of cytokines or NO donors, NO levels was measured by Griess assay and cell survival was evaluated by MTT assay.
RESULT(1) Pretreatment with IL-1 beta and LPS markedly suppressed CCNU cytotoxicity in BT-325 cells with a significant increase in NO production (P<0.05). This function could be inhibited by L-NAME. (2) DETA NONOate suppressed cytotoxicity of CCNU to BT -325 cells in a dose-dependent manner (P<0.05). (3) CCNU co-cultured with SNAP for 24 h showed higher cytotoxic to BT-325 cells(P<0.05).
CONCLUSIONNO partly suppresses cytotoxicity of Lomustine, which might be associated with chemoresistance of BT-325 cells against CCNU in vitro. NO can also slow the degradation of CCNU in water solution.
Antineoplastic Agents, Alkylating ; pharmacology ; Cell Line, Tumor ; Drug Resistance, Neoplasm ; Glioma ; drug therapy ; pathology ; Humans ; Interleukin-1 ; pharmacology ; Lipopolysaccharides ; pharmacology ; Lomustine ; pharmacology ; NG-Nitroarginine Methyl Ester ; pharmacology ; Nitric Oxide ; physiology
8.The mechanism of the anticancer function of M1 macrophages and their use in the clinic.
Chinese Journal of Cancer 2012;31(12):557-563
M1-type macrophages are capable of inducing lysis in various types of cancer cells, but the mechanism of action is unclear. It has been noted that an "unknown protein" produced together with protease by activated macrophages is responsible for this action. Activated M1 macrophages have been recently reported to produce family 18 chitinases, all of which have been named chitotriosidase. Our experiments have demonstrated that family 18 chitinases work together with proteases and can damage various cancer cells both in vitro and in vivo. Thus, in this article, we suggest that the 50-kDa chitotriosidase is the reported "unknown protein". In addition, we discuss how to properly stimulate activated M1 macrophages to produce 50-kDa chitotriosidases and proteases for destroying cancer cells. Because family 19 chitinase has recently been reported to kill cancer cells, we also discuss the possibility of directly using human family 18 chitotriosidase and the humanized plant family 19 chitinase for cancer treatment.
Animals
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Antineoplastic Agents, Alkylating
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pharmacology
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Chitinases
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metabolism
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Cyclophosphamide
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pharmacology
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Hexosaminidases
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metabolism
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Humans
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Immunosuppressive Agents
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pharmacology
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Macrophage Activation
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immunology
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Macrophages
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classification
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enzymology
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immunology
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pathology
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Neoplasms
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immunology
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pathology
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Peptide Hydrolases
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metabolism
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T-Lymphocytes, Regulatory
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metabolism
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Th1 Cells
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metabolism
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Th2 Cells
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metabolism
9.Triptolide-induced suppression of phospholipase D expression inhibits proliferation of MDA-MB-231 breast cancer cells.
Dong Woo KANG ; Ji Young LEE ; Deuk hee OH ; Seon Yang PARK ; Tae Min WOO ; Mi Kyoung KIM ; Mi Hee PARK ; Young Hoon JANG ; Do Sik MIN
Experimental & Molecular Medicine 2009;41(9):678-685
In spite of the importance of phospholipase D (PLD) in cell proliferation and tumorigenesis, little is known about the molecules regulating PLD expression. Thus, identification of small molecules inhibiting PLD expression would be an important advance for PLD-mediated physiology. We examined one such here, denoted "Triptolide", which was identified in a chemical screen for inhibitors of PLD expression using cell assay system based on measurement of PLD promoter activity. Triptolide significantly suppressed the expression of both PLD1 and PLD2 with sub-microM potency in MDA-MB-231 breast cancer cells as analyzed by promoter assay and RT-PCR. Moreover, triptolide abolished the protein level of PLD in a time and dose-dependent manner. Triptolide-induced PLD1 downregulation was also observed in all the cancer cells examined, suggesting a general phenomenon detected in various cancer cells. Decrease of PLD expression by triptolide suppressed both basal and PMA-induced PLD activity. In addition, triptolide inhibited activation of NFkappaB which increased PLD1 expression. Ultimately, downregulation of PLD by triptolide inhibited proliferation of breast cancer cells. Taken together, we demonstrate that triptolide suppresses the expression of PLD via inhibition of NFkappaB activation and then decreases cell proliferation.
Antineoplastic Agents, Alkylating/*pharmacology
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Breast Neoplasms/drug therapy/enzymology
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Cell Line, Tumor
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Cell Proliferation/drug effects
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Diterpenes/*pharmacology
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Epoxy Compounds/pharmacology
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Female
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Gene Expression Regulation, Neoplastic/*drug effects
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Humans
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NF-kappa B/genetics/metabolism
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Phenanthrenes/*pharmacology
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Phospholipase D/*genetics/metabolism
10.Synthesis and antitumor activity of benzoic nitrogen mustard derivatives.
Wen LUO ; Yong-mei ZHAO ; Yu-xia WANG ; Song-qiang XIE ; Jin ZHAO ; Chao-jie WANG
Acta Pharmaceutica Sinica 2007;42(12):1327-1329
To study the effect of isoprenoid and aliphatic saturated alcohols as modificator on benzoic nitrogen mustard, the intermediate 4-[N,N-bis(2-chloroethyl) amino] benzoic acid 4 was prepared in four steps utilizing p-amino benzoic acid as the starting material. Target compounds were synthesized by the catalytic esterification of DCC/DMAP and the structures of the six new esters were characterized by elemental analysis, 1H NMR, 13C NMR and MS. Antitumor activities were evaluated in vitro using MTT assay. The result showed that some derivatives were more potent than the intermediate 4, and compound 5c modified with dodecanol exhibited similar activity to the commercial drug melphalan.
Aminobenzoates
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chemical synthesis
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pharmacology
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Animals
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Antineoplastic Agents, Alkylating
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chemical synthesis
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pharmacology
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CHO Cells
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Cell Line, Tumor
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Cell Proliferation
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drug effects
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Cricetinae
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Cricetulus
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Humans
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Inhibitory Concentration 50
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K562 Cells
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Melanoma, Experimental
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pathology
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Melphalan
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pharmacology
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Nitrogen Mustard Compounds
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chemical synthesis
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pharmacology