A lipophilic copper(II)bis(thiosemicarbazone) labeled with the positron-emitting isotope (61)Cu with hypoxia-selective and radioisotopic activities. With a high membrane permeability and redox potential, (61)Cu-ATSM easily enters and selectively resides in hypoxic cells. The extent of (61)Cu-ATSM retention in tissue is inversely related to the state of tissue oxygenation allowing the quantitation of tissue hypoxia with positron emission tomography (PET).
A methylated tryptophan with anti-immunosuppressive activity. 1-methyl-d-tryptophan inhibits the enzyme indoleamine 2,3-dioxygenase (IDO), which degrades the essential amino acid tryptophan, and may increase or maintain tryptophan levels important to T cell function. Tryptophan depletion is associated with immunosuppression involving T cell arrest and anergy.
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.
An iodine 123-radiolabled small molecule that exhibits high affinity for prostate-specific membrane antigen (PSMA) with potential use in molecular imaging. 123-I-MIP-1095, a radiolabeled glutamate-urea-lysine analogue, selectively binds PSMA, which allows imaging of PSMA-expressing prostate cancer cells with gamma scintigraph. PSMA is a transmembrane glycoprotein highly expressed by malignant prostate epithelial cells and vascular endothelial cells of various solid tumors.
An iodine 131 (I 131) radioconjugate of the synthetic chlorotoxin (CTX) TM-601 with potential antiangiogenic and antineoplastic activities. CTX is a 36 amino acid neurotoxin found in the venom of the giant yellow scorpion Leiurus quinquestriatus that preferentially binds malignant cells of neuroectodermal origin. The recombinant version of this peptide, TM-601, is expressed in and purified from E. coli and then covalently linked to I 131 to produce 131I-TM-601. 131I-TM-601 binds to tumor cells of neuroectodermal origin and is internalized; administered once, it may be used as a radioimaging agent; repeated administration may result in a tumor-specific, cumulative radiocytotoxic dose of I 131. In addition, TM-601 alone, similar to native CTX, may inhibit angiogenesis due to its ability to bind to and inhibit matrix metalloproteinase 2 (MMP-2), an endopeptidase involved in tissue remodeling processes such as angiogenesis.
The orally bioavailable C-4 methyl carbonate analogue of paclitaxel, labeled with radioactive carbon 14, with radioisotope and potential antineoplastic activities. 14C BMS-275183 binds to tubulin and inhibits microtubule disassembly, which may result in cell cycle arrest at the G2/M phase and inhibition of cell division, and subsequently cell death. This agent may be useful for treating multi-drug resistant (MDR) tumors because it does not appear to be a substrate for P-glycoprotein.
A stable derivative of prostaglandin E2 (PGE2) with potential hematopoietic activity. Administration of 16,16 dimethyl-prostaglandin E2 (dmPGE2) appears to lead to increased formation of hematopoietic stem and progenitor cells. Even though the exact mechanism of action has yet to be fully elucidated, this agent may stimulate hematopoiesis by activating the Wnt signaling pathway, which increases cellular levels of beta-catenin, a subunit of the cadherin protein complex.
A radioconjugate and an acetate analog labeled with fluorine F 18 ((18)F-FAC), a positron-emitting isotope, with potential prostate tumor tracer property using positron emission tomography (PET). Although the mechanism of action is unclear, fluorine F 18 acetate preferentially accumulates in tumor tissue, serving as a tracer for imaging tumors with PET. Fluorine 18 has a longer radioactive half-life (110 min) vs. the half-life of carbon-11 acetate (20.4 min). Furthermore, (18)F-FAC showed a rapid clearance from liver and extensive excretion to bile and urine in comparison with carbon-11 acetate, therefore this tracer may be a useful alternative to C-11 acetate for the detection of prostate tumors by PET.
A fluorine-18-labeled acycloguanosine derivative substrate for herpes simplex virus type-1 thymidine kinase (HSV1-tk). 18F-FHBG is used as a reporter probe to image the expression of the herpes simplex virus type-1 thymidine kinase (HSV1-tk) gene in gene transfer therapy. HSV1-tk and and HSV1-tk-metabolized 18F-FHBG co-localize, allowing positron emission tomography (PET) localization of HSV1-tk gene-transfected tissue and the assessment of gene transfer efficiency.
A radiofluorinated 2-nitroimidazole derivative with hypoxia-specific tracer activity. 18F-fluoroazomycin arabinoside is reduced under hypoxic conditions and is often seen in various malignant tumors, forming highly reactive intermediates. In its reduced form, 18F-fluoroazomycin arabinoside covalently binds to macromolecules, thereby accumulating in hypoxic cells and allowing radioisotopic imaging of these particular cells. Compared to 18F-misonidazole, 18F-fluoroazomycin arabinoside has a lower octanol:water partition coefficient; it therefore has less tendency to accumulate in lipophilic tissues and exhibits a faster renal clearance, leading to an improved imaging ability of hypoxic tissue.
A radiotracer consisting of methylcholine labeled with the positron-emitting radioisotope fluorine F 18 (18F-FMCH) with potential imaging use. Upon administration, 18F-fluoromethylcholine incorporates into tumor cells through an active, carrier-mediated transport mechanism for choline and then is phosphorylated intracellularly by choline kinase, an enzyme frequently upregulated in human tumors, yielding phosphoryl 18F-fluoromethylcholine. In turn, phosphoryl 18F-fluoromethylcholine is integrated into phospholipids in the cell membrane as part of phosphatidylcholine. As the proliferation of cancer cells is much higher than normal cells, tumor cells exhibit an increased rate of 18F-FMCH uptake and incorporation, allowing tumor imaging with positron emission tomography (PET).
A radiofluorinated 2-nitroimidazole derivate with hypoxia-specific tracer activity. Misonidazole is reduced under hypoxic conditions and in reduced form covalently binds to macromolecules in hypoxic cells. 18F (fluorine-18) radiofluorination of misonidazole to form 18F-fluoromisonidazole allows radioisotopic imaging of reduced misonidazole bound to macromolecules in hypoxic cells.
A radiotracer containing a pegylated dimeric Arg-Gly-Asp (RGD) peptide (NH2-mini-PEG-E[c(RGDyK)]2 or PRGD2) radiolabeled with fluorine 18F-fluorobenzoate (18F-FB), with potential alphaVbeta3 integrin imaging activity upon positron emission topography (PET). Upon administration, the RGD moiety of 18F-labeled mini-PEG spacered RGD dimer (18F-FPRGD2) binds to alphaVbeta3 integrin. Upon PET, alphaVbeta3-expressing tumor cells can be visualized and the degree of tumor angiogenesis can be determined. This agent exhibits increased integrin receptor binding affinity, tumor cell uptake and increased radiolabeling yield as compared to the non-pegylated form (18F-FRGD2). Integrins, transmembrane glycoproteins, may be upregulated on proliferating tumor vessel endothelial cells and various cancer cells; their overexpression has been associated with neovascularization, differentiation, proliferation of tumor cells, metastasis and an overall poor prognosis.
A deoxyuridine prodrug with potential antineoplastic activity. Upon cellular uptake, 2
A non-anticoagulant heparin derivative in which the 2-O and 3-O sulfate groups of heparin are removed, with potential anti-inflammatory and antineoplastic activity. Upon administration, 2-O, 3-O desulfated heparin (ODSH) prevents the interaction of the receptor for advanced glycation end-products (RAGE) to its ligands, such as advanced glycation end-products (AGEs), Mac-1(CD11b/CD18), the nuclear protein high mobility group box protein-1 (HMGB-1), carboxymethyl lysine-bovine serum albumin (CML-BSA) and members of the S100 calgranulin family. In addition, this agent inhibits the enzymes heparanase, cathepsin G, and human leukocyte elastase, which are involved in inflammation and metastasis. ODSH also inhibits selectins, thereby preventing the adhesion of tumor cells to endothelium and platelets. Altogether, this may inhibit tumor cell invasiveness and metastasis. Unlike heparin, this agent does not induce heparin-induced thrombocytopenia (HIT). RAGE, a receptor belonging to the immunoglobulin superfamily, plays a key role in inflammation and is overexpressed in a variety of cancers.
A radiopharmaceutical agent comprised of a pegylated dimeric arginine-glycine-aspartic acid (RGD)-based peptide labeled with 2-fluoropropionyl, with potential alphaVbeta3 integrin imaging activity upon positron emission topography (PET). The RGD moiety of 2-fluoropropionyl-labeled pegylated dimeric RGD peptide targets and binds to alphaVbeta3 integrin. Upon PET imaging, alphaVbeta3 integrin-expressing tumor cells can be visualized and expression levels can be quantified. Compared to other fluorine F 18 labeled RGD-containing peptides, this agent shows increased affinity to alphaVbeta3 integrin, enhanced tumor uptake as well as improved pharmacokinetics. alphaVbeta3 integrin, overexpressed on certain tumor cells and tumor endothelial cells, plays a key role in angiogenesis, tumor proliferation and survival.
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.
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.
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.
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.
A hapten-carrier immunoconjugate composed of the hapten trans-3
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.
A ring-substituted amphetamine derivative, structurally related to the hallucinogen mescaline, with entactogenic, neurotoxic, and motor-stimulatory activities. 3,4-methylenedioxymethamphetamine (MDMA) produces an acute, rapid enhancement in both the release of serotonin from and the inhibition of serotonin reuptake by serotonergic nerve endings in the brain. Once within the cell, MDMA depletes stores of tryptophan hydroxylase (TPH) via acute oxidative inactivation; in turn, depleted stores of TPH leave cell terminals open to damage from oxidative stress, possibly a source of MDMA neurotoxicity. This agent also induces norepinephrine, dopamine, and acetylcholine release and can act directly on a number of receptors, including alpha 2-adrenergic and 5-hydroxytryptamine (5-HT) 2A receptors. MDMA may suppress the dyskinesia associated with long-term use of L-dopamine (L-DOPA) without affecting the efficacy of L-DOPA treatment.
A synthetic analogue of nucleoside uridine lacking a ring nitrogen in the 3-position. 3-deazauridine inhibits cytidine synthase, thereby reducing intracellular levels of cytidine and deoxycytidine and disrupting DNA and RNA synthesis. This agent may trigger apoptosis and enhance differentiation of neoplastic cells..
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),
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.
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.
A radioconjugate consisting of the 7 amino acid peptide sequence ASYNYDA (GI heptapeptide) and labeled with the fluorescent dye fluorescein isothiocyanate (5-FITC), with potential imaging activity. Upon topical application to the esophageal mucosa using a spray, the heptapeptide moiety of 5-FITC-labeled GI-heptapeptide binds to abnormal cells in the esophagus; the FITC moiety allows for imaging with white light and the area of interest for biopsies can then be visualized.
A fluorinated pyrimidine analogue antimetabolite 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 and the inhibition of DNA synthesis and cell division. FUTP competes with uridine triphosphate (UTP) for incorporation into the RNA strand, which results in the inhibition of RNA and protein synthesis and cell proliferation. Other fluorouracil metabolites also get incorporated into both DNA and RNA, with further inhibition of cellular growth.
A topical formulation containing 0.5 % of antimetabolite 5-fluorouracil (5-FU) and 10% of salicylic acid, with potential antimitotic and keratolytic activity. Upon cutaneous application, 5-FU in the 5-fluorouracil/salicylic acid topical solution impedes pyrimidine metabolism thereby inhibiting cell growth, while the salicylic acid induces anti-inflammatory response and results in keratolytic effect. This may result in the breakdown of keratinocytes and prevent proliferation of keratinocytes locally.
The fluorine-18 (18F)-radiolabeled pyrimidine analog 5-fluorouracil (5-FU) with positron-emitting activity. Upon administration, 5-[18F]fluorouracil distribution in tumor tissue may be measured with positron emission tomography (PET). The degree of 5-[18F]fluorouracil uptake in tumor tissue may help to predict the response to 5-fluorouracil-based chemotherapy or to determine the response to other therapeutic agents used to treat 5-FU-sensitive tumors.
An equimolar gas mixture of oxygen (O2) and nitrous oxide (N2O) with potential analgesic activity. Upon inhalation, 50% oxygen/50% nitrous oxide premix produces rapidly reversible analgesia. The exact mechanism through which nitrous oxide exerts its analgesic effect has yet to be fully elucidated, but it appears to be associated with the neuronal release of endogenous opioid peptides.
A racemic mixture of the enantiomers of a synthetic alpha-lipoic lipoic acid analogue with potential chemopreventive and antineoplastic activities. Although the exact mechanism of action is unknown, 6,8-bis(benzylthio)octanoic acid has been shown to inhibit metabolic and regulatory processes required for cell growth in solid tumors. Both enantiomers in the racemic mixture exhibit antineoplastic activity.
A synthetic triazine analogue of uridine with antimetabolite activity. 6-azauridine inhibits de novo pyrimidine synthesis and DNA synthesis and is converted intracellularly into mono, di-, and triphosphate derivatives, which incorporate into RNA and inhibit protein synthesis.
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.
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.
An ointment formulation containing the sulfate salt of 8-hydroxyquinoline in a petrolatum and lanolin base with skin-protecting activity. Upon topical application, 8-hydroxyquinoline sulfate exhibits antiseptic activity while lanolin moisturizes and softens skin.
A topical gel containing a peptide derived from the human papillomavirus (HPV). Application of 851B gel may stimulate the host immune system to trigger a cytotoxic T-lymphocyte response to cells that express HPV.
A synthetic imidazoquinoline Toll-like receptor 7 (TLR7) agonist with immunostimulating and potential antitumor activities. TLR7 agonist 852A binds to and activates TLR7, thereby stimulating plasmacytoid dendritic cells (pDC) through the TLR7-MyD88-dependent signaling pathway. Activation of pDC results in secretion of interferon alpha, the production of proimflammatory cytokines, the upregulation of co-stimulatory molecules, and enhanced T and B-cell stimulatory responses.
A radiolabeled macromolecule consisting of the chelating agent diethylenetriamine pentaacetic acid (DTPA) and mannose each attached to a dextran backbone and labeled with metastable technetiumTc-99 (Tc-99m), with mannose binding and radioisotopic activities. Upon injection, the mannose moiety of 99mTc-DTPA-mannosyl-dextran binds to mannose-binding protein (MBP). As MBPs reside on the surface of dendritic cells and macrophages, this gamma-emitting macromolecule tends to accumulate in lymphatic tissue where it may be imaged using gamma scintigraphy. This agent exhibits rapid clearance from the injection site, rapid uptake and high retention within the first draining lymph node, and low uptake by the remaining lymph nodes. MBP is a C-type lectin that binds mannose or fucose carbohydrate residues, such as those found on the surfaces of many pathiogens, and once bound activates the complement system.
A radioconjugate consisting of the positron emitting radioisotope fluorine F 18 conjugated to the substance P antagonist receptor quantifier (SPA-RQ) used in radioimaging. [18F]-labeled substance P antagonist receptor quantifier is an antagonist of the neurokinin 1 (substance P) receptor (NK1R) and can function as a positron emission tomography (PET) imaging agent for detecting NK1R-expressing cells and tissues. NK1Rs are frequently expressed on the plasma membranes of tumor cells from glioblastoma and breast and pancreatic carcinomas.
A small molecular-weight, malonic acid-based probe [(2-(5-fluoro-pentyl)-2-methyl-malonic acid or ML-10] labeled with the radioactive isotope fluorine F 18 with potential apoptosis radioimaging use. Upon administration, [F18]-ML-10 binds selectively to apoptotic cells due to apoptotic cell membrane features that differ from those of normal, healthy and necrotic cell membranes. Upon entering the apoptotic cell, this agent accumulates within the cytoplasm where it can be imaged using positron emission tomography (PET). Detection of apoptotic cells using this imaging technology may be useful in monitoring tumor responses to cytotoxic therapies. ML-10 appears to mimic the alkyl-malonic acid motif present in gamma -carboxyglutamic (Gla), an amino acid that plays a crucial role in the binding of clotting factors to negatively-charged phospholipids exposed on the surfaces of apoptotic cells.
A deoxycytidine analog and high-affinity substrate for deoxycytidine kinase (DCK), labeled with fluorine F 18, with potential diagnostic activity upon positron emission tomography (PET) imaging. [18F]L-FAC is preferentially taken up by and accumulated in cells with high deoxycytidine kinase (DCK) levels, such as in tumor cells with dysregulated nucleoside metabolism. Upon uptake through the nucleoside transporter, [18F]L-FAC is phosphorylated by DCK and, subsequently, the 18F moiety can be visualized upon PET imaging. As many nucleoside analog prodrugs are chemotherapeutic agents that require DCK for activation, [18F]L-FAC can potentially be used as a marker to predict chemotherapeutic efficacy of these prodrugs. In addition, as DCK is upregulated in certain immune cells, such as activated T-cells, [18F]L-FAC can also be used to measure immune activation in response to immunomodulating agents. DCK, a rate-limiting enzyme in the nucleoside salvage pathway for DNA synthesis, is overexpressed in certain solid tumors, lymphoid and myeloid malignancies and certain immune cells, such as proliferating T-lymphocytes.
A radioconjugate composed of 2
A 2-nitroimidazole labeled with the positron-emitting radioisotope fluorine F 18. HX4, the 2-nitroimidazole moiety of [F-18]HX4, is selectively bioreduced and bound in hypoxic tumor cells, permitting the imaging of hypoxic tumor cells with positron emission tomography (PET).
A radiopharmaceutical consisting of a sulfonamide covalently attached to the positron-emitting isotope fluorine F 18 with CA-IX-binding and radioisotopic activities. Upon administration, the sulfonamide moiety of [F18]VM4-037 binds to the cell-surface tumor-associated antigen (TAA) carbonic anhydrase IX isoenzyme (CA-IX); CA-IX-expressing tumor cells can then be visualized using positron emission tomography (PET). CA-IX has been found to be elevated in a variety of hypoxic tumors; elevated CA-IX has been positively correlated with tumor growth, tumor invasion and poor prognosis.