Antineoplastic agents 0-9

• 10-deacetyltaxol - An analog of paclitaxel with antineoplastic activity. 10-Deacetyltaxol binds to and stabilizes the resulting microtubules, thereby inhibiting microtubule disassembly which results in cell- cycle arrest at the G2/M phase and apoptosis.

• 117-126:fgf-5 peptide - A fragment of fibroblast growth factor-5 (FGF-5). Originally isolated from a renal cell carcinoma cell line that overexpressed FGF-5, FGF-5:117-126 peptide is recognized by tumor infiltrating cytotoxic T lymphocytes. Overexpressed by several cancer cell types, this peptide is being tested as a potential target for antineoplastic immunotherapies.

• 11c topotecan - A semisynthetic derivative of camptothecin, a cytotoxic, quinoline-based alkaloid extracted from the Asian tree Camptotheca acuminata radiolabeled with carbon 11 (11C) with antineoplastic and radiotracer properties. During the S phase of the cell cycle, topotecan inhibits topoisomerase I activity by stabilizing the cleavable complex between topoisomerase I and DNA, resulting in DNA breaks that inhibit DNA replication and trigger apoptotic cell death. Quantitation of 11C topotecan accumulated in tumor tissues by positron emission tomography (PET) may help predict responses to topotecan therapy.

• 11d10 alugel anti-idiotype monoclonal antibody - A monoclonal anti-idiotype antibody adsorbed to aluminum hydroxide gel (AluGel) with potential antineoplastic activity. 11D10 AluGel anti-idiotype monoclonal antibody mimics the human milk fat globule (HMFG) antigen found in breast and other cancers. Vaccination with 11D10 AluGel anti-idiotype monoclonal antibody may induce a host antibody response against tumor cells positive for the HMFG antigen.

• 12-allyldeoxoartemisinin - A semi-synthetic analogue of Artemisinin - a sesquiterpene lactone extracted from the dry leaves of Artemisia Annua (sweet wormwood) used as anti-malaria agent. Limited data is available on Artemisinin antineoplastic activity.

• 13-deoxydoxorubicin - An analogue of the anthracycline antineoplastic antibiotic doxorubicin. 13-Deoxydoxorubicin intercalates DNA and interacts with topoisomerase II, thereby inhibiting DNA replication and repair and RNA and protein synthesis. This agent was designed to be a non-cardiotoxic anthracycline antibiotic.

• 14c bms-275183 - An orally bioavailable taxane compound, a C-4 methyl carbonate analogue of paclitaxel, labeled with radioactive carbon 14, with potential antineoplastic and radioimaging activities. BMS-275183 binds to tubulin and as a result inhibits microtubule disassembly or assembly. This leads to cell cycle arrest at the G2/M phase, thereby resulting in an inhibition of cell division and ultimately cell death. BMS-275183 may be useful for treating multi-drug resistant tumors as it does not appear to be a substrate for P-glycoprotein.

• 17beta-hydroxysteroid dehydrogenase type 5 inhibitor asp9521 - A selective, orally bioavailable inhibitor of 17beta-hydroxysteroid dehydrogenase type 5 (17bHSD5, aldo-keto reductase 1C3; AKR1C3), with potential antineoplastic activity. Upon administration, ASP9521 selectively binds to and inhibits the activity of 17bHSD5. This prevents the conversion of the adrenal androgens dehydroepiandrosterone and androstenedione into 5-androstenediol and testosterone. By blocking testosterone production, ASP9521 may inhibit the growth of testosterone-dependent cancers such as castration-resistant prostate cancer (CRPC). 17bHSD5, expressed both in normal prostate tissue and in prostate cancer (PC), plays a crucial role in persistent production of androgens despite castration; its expression is associated with increased malignancy of PC.

• 2,6-diaminopurine - One of a number of organic compounds that share a similar purine structure and possess antiviral and antitumor properties. 2,6-Diaminopurine nucleosides are versatile synthetic precursors for specific N-6 modifications of antiviral and antitumor agents.

• 2,6-dimethoxyquinone - A methoxy-substituted benzoquinone and bioactive compound found in fermented wheat germ extracts, with potential antineoplastic and immune-enhancing activity. 2,6-Dimethoxyquinone (2,6-DMBQ) inhibits anaerobic glycolysis thereby preventing cellular metabolism and inducing apoptosis. As cancer cells use the anaerobic glycolysis pathway to metabolize glucose and cancer cells proliferate at an increased rate as compared to normal, healthy cells, this agent is specifically cytotoxic towards cancer cells. In addition, 2,6-DMBQ exerts immune-enhancing effects by increasing natural killer (NK) cell and T-cell activity against cancer cells.

• 2-deoxy-d-glucose - A non-metabolizable glucose analog in which the hydroxyl group at position 2 of glucose is replaced by hydrogen, with potential glycolysis inhibiting and antineoplastic activities. Although the exact mechanism of action has yet to be fully elucidated, upon administration of 2-deoxy-D-glucose (2-DG), this agent competes with glucose for uptake by proliferating cells, such as tumor cells. 2-DG inhibits the first step of glycolysis and therefore prevents cellular energy production, which may result in decreased tumor cell proliferation.

• 2-ethylhydrazide - A podophyllic acid derivative of podophyllotoxin, a substance extracted from the mandrake root Podophyllum peltatum. Possessing potent antineoplastic properties, 2-ethylhydrazide binds to and inhibits topoisomerase II and its function in ligating cleaved DNA molecules, resulting in the accumulation of single- or double-strand DNA breaks, the inhibition of DNA replication and transcription, and apoptotic cell death.

• 2'-f-ara-deoxyuridine - A deoxyuridine prodrug with potential antineoplastic activity. Upon cellular uptake, 2'-F-ara-deoxyuridine (FAU) is phosphorylated by thymidine kinase to FAU monophosphate and subsequently methylated in the 5'-position by thymidylate synthase (TS) to its activated form, 1-(2-deoxy-2-fluoro-beta-D-arabinofuranosyl) 5-methyluracil monophosphate (FMAUMP). FMAUMP is incorporated into DNA leading to an inhibition of DNA synthesis and so cell growth. The catalytic activity of TS is critical to activation of FAU and subsequent incorporation into DNA. FAU may be beneficial in the case of tumors with high TS activity that are resistant to TS inhibitors.

• 2-fluoroadenine - A fluorinated heterocyclic 2-ring compound. 2-fluoroadenine is the base moiety for many carbocyclic and acyclic nucleoside analogues, which may be used in antineoplastic studies.

• 2-fluorofucose-containing sgn-2ff - An orally bioavailable fluorinated analog of fucose that is a protein fucosylation inhibitor, with potential antineoplastic and immunomodulating activities. Upon administration of SGN-2FF, 2-fluorofucose (2-FF) mimics fucose and is converted to guanosine diphosphate (GDP)-2FF, which prevents the formation of the fucosylation substrate GDP-fucose, and the incorporation of fucose into glycoproteins by fucosyltransferase. As fucosylation of glycoproteins plays a key role in many biological processes, such as protein function, receptor binding, cell signaling and cellular adhesion, and is essential for tumor progression, blocking fucosylation decreases tumor cell growth. In addition, blocking fucosylation of monoclonal antibodies generates fucose-deficient antibodies that exert enhanced antibody-dependent cell-mediated cytotoxicity (ADCC).

• 2g-1 tcr retroviral vector-transduced lymphocytes - A preparation of autologous human T-lymphocytes isolated from renal cell cancer (RCC) patient and transduced with 2G-1 TCR, a retroviral vector encoding the alpha and beta chains of a T-cell receptor that recognizes TNF-related apoptosis inducing ligand (TRAIL) bound to death receptor 4 (DR4), with potential immunostimulating and antineoplastic activities. After transduction, expansion in culture, and introduction into the RCC patient, 2G-1 TCR retroviral vector-transduced lymphocytes may stimulate a cytotoxic T lymphocyte (CTL) response against RCC cells with TRAIL bound to DR4 on their surfaces. TRAIL, a member of the TNF superfamily, is a homotrimeric type II membrane protein that rapidly induces oligomerization of receptor intracellular death domains and apoptosis in a variety of tumor cells when bound to its receptors; DR4 (TRAIL receptor 1), a member of the TNF receptor family, is overexpressed by a variety of malignant cell types.

• 2-hydroxyestradiol - A metabolite formed during the metabolism of 17beta-estradiol by hydroxylation of the carbon at position 2 by the CYP450 enzymes 1A1/1A2. Theoretically, 2-hydroxyestradiol (2-OHE2) is able to undergo redox cycling, which generates active radicals and induces DNA damage; however, this estradiol metabolite is very unstable in vivo and is quickly inactivated by catechol-O-methyltransferase (COMT)-mediated O-methylation and converted to 2-methoxyestradiol (2-MeE2). 2-MeE2 exerts antineoplastic activities through its estrogen receptor antagonistic effect and the induction of apoptosis in susceptible cancer cells.

• 2-hydroxyestrone - A metabolite formed during the catabolism of estrone by the liver through the hydroxylation of the carbon at position 2 by cytochrome P450 (CYP) enzymes, including CYP1A1 and 1A2, with potential anticarcinogenic activity. The mechanism of action for the antitumor activity of 2-hydroxyestrone is not known but this metabolic product has minimal estrogenic activity compared to the parent compound and other estrone metabolites. Additionally, O-methylation of this compound produces 2-methoxyestradiol (2-MeOE2), which is a potent inhibitor of both cell proliferation and angiogenesis.

• 2-hydroxyflutamide depot - A depot formulation containing a bioresorbable, controlled-release, calcium sulphate-based paste of the nonsteroidal antiandrogen 2-hydroxyflutamide (2-HOF) with potential antineoplastic activity. Upon injection into the tumor site in the prostate, 2-hydroxyflutamide depot slowly releases 2-HOF, which competitively binds to androgen receptors (ARs), blocking the binding of dihydrotestosterone (DHT). This may inhibit androgen-dependent DNA and protein synthesis, resulting in tumor cell growth arrest and decreased cellular proliferation. In addition, 2-HOF inhibits nuclear uptake of androgen in androgen-responsive tissues.

• 2-hydroxyoleic acid - An orally bioavailable, synthetic analog of the fatty acid oleic acid, with potential antitumor activity. Upon administration, 2-hydroxyoleic acid (2OHOA) activates sphingomyelin synthase (SMS), thereby increasing the concentration of sphingomyelin (SM) and diacylglycerol (DAG) in the tumor cell membrane and decreasing membrane levels of phosphatidylethanolamine (PE) and phosphatidylcholine (PC). This restores the normal, healthy levels and ratios of membrane lipids. By restoring normal membrane lipid structure and composition, this agent inhibits membrane-protein associated signaling and the aberrant activity of signaling pathways in certain tumor cells, including the Ras/MAPK and PI3K/AKt pathways. This inhibits tumor cell proliferation, induces tumor cell differentiation, and eventually can cause cell death.

• 2-methoxyestradiol - An orally bioavailable estradiol metabolite with potential antineoplastic activity. 2-Methoxyestradiol inhibits angiogenesis by reducing endothelial cell proliferation and inducing endothelial cell apoptosis. This agent also inhibits tumor cell growth by binding to tubulin, resulting in antimitotic activity, and by inducing caspase activation, resulting in cell cycle arrest in the G2 phase, DNA fragmentation, and apoptosis.

• 2-methoxyestradiol nanocrystal colloidal dispersion - An orally bioavailable liquid formulation containing the small molecule 2-methoxyestradiol with potential antineoplastic activity. 2-Methoxyestradiol, a naturally occurring estradiol metabolite, exerts its antitumor effect by inhibiting endothelial cells as well as tumor cells through multiple mechanisms. This agent binds to tubulin and disrupts microtubule formation, thereby preventing mitosis and subsequent cellular proliferation. In addition, 2-methoxyestradiol induces caspase activation, resulting in cell cycle arrest in G2 phase and apoptosis in due course. This agent also down-regulates hypoxia inducible factor-one alpha (HIF-1a). The nanocrystal colloidal dispersion increases the absorption of 2-methoxyestradiol, thereby improving its bioavailability, which results in enhanced drug plasma levels.

• 2-methoxyestrone - A metabolite formed during the methylation of 2-hydroxyestrone (2-OHE1) by catechol-O-methyltransferase (COMT), with potential anticarcinogenic and minimal estrogen activities. The mechanism of action for the antitumor activity of 2-methoxyestrone (2-OMeE1) is not known. A high 2-methoxyestrone (2-OMeE1)/2-OHE1 ratio indicates higher methylation efficiency and correlates with a lower cancer risk.

• 3'-c-ethynylcytidine - A synthetic cytidine nucleoside containing a covalently bound ethynyl group with potential antineoplastic and radiosensitizing activities. 3'-C-ethynylcytidine is metabolized in tumor cells to ethynylcytidine triphosphate (ECTP), which inhibits RNA synthesis by competitive inhibition of RNA polymerases I, II and III; subsequently, RNase L is activated, resulting in apoptosis. RNase L is a potent antiviral and antiproliferative endoribonuclease that cleaves singled stranded RNA, causes 28s rRNA fragmentation, and activates Janus Kinase (JAK), a mitochondrial-dependent apoptosis signaling molecule.

• 3'-da phosphoramidate nuc-7738 - A phosphoramidate derivative of the monophosphate form of cordycepin (3'-deoxyadenosine; 3'-dA), an adenosine derivative first isolated from Cordyceps sinensis, with potential antineoplastic, antioxidant, and anti-inflammatory activities. Upon administration and cellular uptake of NUC-7738 by passive diffusion, cordycepin monophosphate (3'-dAMP) is converted into its active anti-cancer metabolite 3'-deoxyadenosine triphosphate (3'-dATP). 3'-dATP functions as a ribonucleoside analogue and competes with ATP during transcription. Therefore, this agent causes RNA synthesis inhibition, inhibits cellular proliferation, and induces apoptosis. Also, 3'-dAMP activates AMP-activated protein kinase (AMPK) and reduces mammalian target of rapamycin (mTOR) signaling. This prevents the hyperphosphorylation of the translation repressor protein 4E-BP1. This results in the induction of tumor cell apoptosis and a decrease in tumor cell proliferation. mTOR, a serine/threonine kinase belonging to the phosphatidylinositol 3-kinase (PI3K)-related kinase (PIKK) family, plays an important role in the PI3K/AKT/mTOR signaling pathway that regulates cell growth and proliferation, and its expression or activity is frequently dysregulated in human cancers. Compared to cordycepin alone, the addition of the phosphoramidate moiety may overcome cancer resistance and allow for greater cytotoxicity as NUC-7738 does not require a nucleoside transporter for cellular uptake, is independent of enzymatic activation by adenosine kinase (AK) and is not susceptible to enzymatic degradation by adenosine deaminase (ADA). Altogether, this may help overcome cancer resistance to cordycepin.

• 4h11-28z/fil-12/egfrt-expressing autologous t-lymphocytes - A preparation of genetically modified autologous T-lymphocytes transduced with a retroviral vector expressing a chimeric antigen receptor (CAR) targeting the human tumor-associated antigen (TAA) MUC16ecto and encoding the human pro-inflammatory cytokine interleukin-12 (IL-12), fused to the signaling domain of the zeta chain of the TCR/CD3 complex (28z), and a truncated form of the human epidermal growth factor receptor (EGFRt), with potential immunostimulating and antineoplastic activities. Upon intravenous administration, 4H11-28z/fIL-12/EGFRt-expressing autologous T-lymphocytes are directed to and induce selective toxicity in MUC16-expressing tumor cells. In addition, the T-cells secrete IL-12 which induces secretion of interferon-gamma, promotes the activation of natural killer cells (NKs), and induces cytotoxic T-cell responses against tumor cells, which may result in immune-mediated tumor cell death and inhibition of tumor cell proliferation. Devoid of both ligand binding domains and tyrosine kinase activity, the expressed EGFRt both facilitates in vivo detection of the administered, transduced T-cells and can promote elimination of those cells through a cetuximab-induced antibody-dependent cellular cytotoxicity (ADCC) response. MUC16, a transmembrane protein and glycosylated mucin, is overexpressed on the cell surface of the majority of ovarian cancer cells but not on healthy cells. MUC16ecto is the extracellular portion of MUC-16 and is the part that is retained by cells after cleavage of CA-125.

• 4'-iodo-4'-deoxydoxorubicin - An iodinated doxorubicin analogue with antiamyloid activity. 4'-Iodo-4'-deoxydoxorubicin (IDOX) binds with high affinity to five types of natural amyloid fibrils including immunoglobulin light chains, amyloid A, transthyretin (methionine-30 variant), beta-protein (Alzheimer), and beta2-microglobulin. This agent may inhibit fibril growth, increasing the solubility of amyloid tissue deposits and facilitating their clearance. IDOX has also been shown to insulin amyloid fibrillogenesis in vitro.

• 4-nitroestrone 3-methyl ether - A synthetic derivative of estradiol. 4-nitroestrone 3-methyl ether inhibits estrogen sulfotransferase (EST), a progesterone-induced secretory endometrial enzyme which affects estrogen receptor levels. This agent has been shown to be an effective growth inhibitor of some chemically induced animal mammary tumors.

• 4-peptide melanoma vaccine - An emulsion of 4 melanoma peptides with potential immunomodulating and antineoplastic activities. Upon vaccination, 4-peptide melanoma vaccine may stimulate an immune response against 4 different melanoma associated antigens. This may lead to a reduction in tumor cell proliferation of cancer cells expressing these antigens.

• 4-thio-2-deoxycytidine - An orally bioavailable 4-thio modified 2-deoxycytidine analog, with potential antineoplastic activity. Upon administration of 4-thio-2-deoxycytidine (TdCyd), this cytidine analog gets incorporated into DNA during replication and inhibits the activity of DNA methyltransferase 1 (DNMT1), which blocks DNA hypermethylation. This results in DNMT1 depletion, hypomethylation of DNA, and the reactivation of tumor suppressor genes that were silenced by hypermethylation; this results in antitumor activity and an inhibition of tumor cell proliferation.

• 5-aza-4'-thio-2'-deoxycytidine - An orally bioavailable, nucleoside analog and DNA methyltransferase I (DNMT1) inhibitor, with potential DNA hypomethylating and antineoplastic activities. Upon administration, 5-aza-4'-thio-2'-deoxycytidine (Aza-TdC) gets incorporated into DNA, where it binds to the active site of DNMT1, a maintenance methyltransferase that contributes to the hypermethylation and silencing of tumor suppressor genes. The formation of covalent DNMT1-DNA complexes inhibits DNMT1, prevents DNA methylation of CpG sites, causes CpG demethylation, and results in the re-expression and re-activation of silenced tumor suppressor genes. This inhibits tumor cell proliferation. DNMT1, overactivated in tumor cells, plays a key role in tumor cell proliferation.

• 5-fluoro-2-deoxycytidine - An antimetabolite consisting of a fluorinated pyrimidine analog with potential antineoplastic activity. As a prodrug, 5-fluoro-2-deoxycytidine is converted by intracellular deaminases to the cytotoxic agent 5-Fluorouracil (5-FU). 5-FU is subsequently metabolized to active metabolites including 5-fluoro-2-deoxyuridine monophosphate (FdUMP) and 5-fluorouridine triphosphate (FUTP). FdUMP binds to and inhibits thymidylate synthase, thereby reducing the production of thymidine monophosphate, which leads to depletion of thymidine triphosphate. This inhibits DNA synthesis and cell division. FUTP competes with uridine triphosphate for incorporation into the RNA strand thus leading to an inhibition of RNA and protein synthesis. Other fluorouracil metabolites also get incorporated into both DNA and RNA, thereby further hampering cellular growth.

• 6 melanoma helper peptide vaccine - A multi-epitope vaccine containing the following six class II MHC-restricted peptides: gp100, MelanA/MART-1, two tyrosinase peptides, and the cancer/testis antigens MAGE-A3 and MAGE-A1,2,3,6, with potential antineoplastic activity. Upon administration, melanoma helper peptides induce an antigen-specific, Th1-dominant, CD4+ T-cell response, potentially augmenting cytotoxic T-cell (CTL) responses and maintaining immunologic memory against tumor cells expressing melanoma-specific antigens. The 6MHP vaccine may also induce a CD8+ T-cell response through epitope spreading, potentially priming subsequent immune responses against tumor cells.

• 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases isoform 3 inhibitor act-pfk-158 - An inhibitor of 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatases (PFK-2/FBPase) isoform 3 (PFKFB3) and derivative of 3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO), with potential antineoplastic activity. Upon administration, PFKFB3 inhibitor PFK-158 binds to and inhibits the activity of PFKFB3, which leads to the inhibition of both the glycolytic pathway in and glucose uptake by cancer cells. This prevents the production of macromolecules and energy that causes the enhanced cellular proliferation in cancer cells as compared to that of normal, healthy cells. Depriving cancer cells of nutrients and energy leads to the inhibition of cancer cell growth. PFKFB3, an enzyme that catalyzes the conversion of fructose-6-phosphate to fructose-2,6-bisphosphate, is highly expressed and active in human cancer cells; it plays a key role in increasing both glycolytic flux in and proliferation of cancer cells.

• 7-cyanoquinocarcinol - A semisynthetic analogue of the Streptomyces melanovinaceus-derived tetracyclic antitumor antibiotic quinocarmycin with potential antineoplastic activity. Quinocarmycin belongs to the naphthyridinomycin/saframycin class of antitumor antibiotics. These antibiotics appear to act through DNA alkylation.

• 7-ethyl-10-hydroxycamptothecin -

• 7-hydroxystaurosporine - A synthetic derivative of staurosporine with antineoplastic activity. 7-hydroxystaurosporine inhibits many phosphokinases, including the serine/threonine kinase AKT, calcium-dependent protein kinase C, and cyclin-dependent kinases. This agent arrests tumor cells in the G1/S of the cell cycle and prevents nucleotide excision repair by inhibiting the G2 checkpoint kinase chk1, resulting in apoptosis.

• 8-azaguanine - A purine analogue with potential antineoplastic activity. 8-Azaguanine interferes with the modification of transfer ribonucleic acid (tRNA) by competing with guanine for incorporation into tRNA catalyzed by the enzyme tRNA-guanine ribosyltransferase (tRNA-guanine transglycosylase). Altered guanine modification of tRNA has been implicated in cellular differentiation and neoplastic transformation. 8-Azaguanine also inhibits the formation of 43S and 80S initiation complexes, thereby interfering with initiation of translation and inhibiting protein synthesis. This agent inhibits tumor cell growth and stimulates cell differentiation.

• 8-chloroadenosine - An antimetabolite and a chlorine derivative of the purine nucleoside adenosine, with potential antineoplastic activity. Upon administration, 8-chloro-adenosine is phosphorylated to form 8-chloro-adenosine triphosphate (8-chloro-ATP), which functions as a ribonucleoside analogue and competes with ATP during transcription. Therefore, this agent causes RNA synthesis inhibition, inhibits cellular proliferation, and induces apoptosis.

• 9-ethyl 6-mercaptopurine - A synthetic alkyl derivative prodrug of the antineoplastic agent 6-mercaptopurine (6-MP). In vivo, 9-ethyl 6-mercaptopurine appears to be converted to 6-MP, which substitutes for the normal nucleoside and fraudulently incorporates into DNA and inhibits de novo purine synthesis, thereby inducing cell death.

• 9h-purine-6thio-98d - An antimetabolite analogue of purine with antineoplastic and immuno-suppressant properties. 9H-Purine-6Thio-98D substitutes for the normal nucleoside and fraudulently incorporates into DNA and inhibits de novo purine synthesis, thereby inducing cell death. In vivo, this agent, also known as 6MP-arabinoside, may occur as a metabolite of the antineoplastic agent mercaptopurine.

• A2a receptor antagonist eos100850 - An orally bioavailable immune checkpoint inhibitor and antagonist of the adenosine A2A receptor (A2AR; ADORA2A), with potential immunomodulating and antineoplastic activities. Upon administration, A2AR antagonist EOS100850 selectively binds to and inhibits A2AR expressed on T-lymphocytes. This prevents tumor-released adenosine from interacting with the A2A receptors, thereby blocking the adenosine/A2AR-mediated inhibition of T-lymphocytes. This results in the proliferation and activation of T-lymphocytes, and stimulates a T-cell-mediated immune response against tumor cells. A2AR, a G protein-coupled receptor, is highly expressed on the cell surfaces of T-cells and, upon activation by adenosine, inhibits their proliferation and activation. Adenosine is often overproduced by cancer cells and plays a key role in immunosuppression.

Alphabetic list of antineoplastic agents - 0-9 - A1 - A2 - A3 - A4 - A5 -A6 - B - C - D - E - F - G - H - I - JK - L - M - NO - PQ - R - S - T - UVW - XYZ