pyrophosphate and Leukemia

Despite the synthesis of hundreds of new platinum(II) and platinum(IV)-based complexes each year as potential anticancer drugs, only three have received world-wide approval: cisplatin, carboplatin and oxaliplatin. The next big advance in platinum-based chemotherapy is not likely to come from the development of new drugs, but from the controlled and targeted delivery of already approved drugs or those in late stage clinical trials. Encapsulation of platinum drugs inside macromolecules has already demonstrated promise, and encapsulation within cucurbit[n]urils has shown particular potential. Partial or full encapsulation within cucurbit[n]urils provides steric hindrance to drug degradation by peptides and proteins, and the use of different sized cucurbit[n]urils allows for the tuning of drug release rates, cytotoxicity and toxicity.

Topics: Animals; Anticarcinogenic Agents; Bridged-Ring Compounds; Cell Line, Tumor; Diphosphates; Drug Combinations; Drug Delivery Systems; Humans; Leukemia; Mice; Polyethylenes

The Japanese marine sponge Discodermia calyx contains a major cytotoxic compound, calyculin A, which exhibits selective inhibition of protein phosphatases 1 and 2A. It has long been used as a chemical tool to evaluate intracellular signal transduction regulated by reversible protein phosphorylation. We describe the identification of the biosynthetic gene cluster of calyculin A by a metagenome mining approach. Single-cell analysis revealed that the gene cluster originates in the symbiont bacterium 'Candidatus Entotheonella' sp. A phosphotransferase encoded in the gene cluster deactivated calyculin A to produce a newly discovered diphosphate, which was actually the biosynthetic end product. The diphosphate had been previously overlooked because of the enzymatic dephosphorylation that occurred in response to sponge tissue disruption. Our work presents what is to our knowledge the first evidence for the biosynthetic process of calyculin A along with a notable phosphorylation-dephosphorylation mechanism to regulate toxicity, suggesting activated chemical defense in the most primitive of all multicellular animals.

Topics: Animals; Antineoplastic Agents; Diphosphates; Drug Screening Assays, Antitumor; HeLa Cells; Humans; Leukemia; Marine Toxins; Metagenome; Mice; Molecular Sequence Data; Multigene Family; Organophosphates; Oxazoles; Phosphorylation; Phosphotransferases; Phylogeny; Polyketide Synthases; Porifera; RNA, Ribosomal, 16S; Symbiosis

Advances in the treatment of acute leukemia have resulted in significantly improved remission rates, although disease relapse poses a significant risk. By utilizing sensitive, non-invasive imaging guidance, detection of early leukemic infiltration and the extent of residual tumor burden after targeted therapy can be expedited, leading to more efficient treatment planning. We demonstrated marked survival benefit and therapeutic efficacy of a new-generation vascular disrupting agent, combretastatin-A1-diphosphate (OXi4503), using reporter gene-imaging technologies and mice systemically administered luc+ and GFP+ human leukemic cells (LCs). Before treatment, homing of double-transduced cells was serially monitored and whole-body cellular distributions were mapped using bioluminescence imaging (BLI). Imaging findings strongly correlated with quantitative GFP expression levels in solid organs/tissues, suggesting that the measured BLI signal provides a highly sensitive and reliable biomarker of tumor tissue burden in systemic leukemic models. Such optical technologies can thereby serve as robust non-invasive imaging tools for preclinical drug discovery and for rapidly screening promising therapeutic agents to establish potency, treatment efficacy and survival advantage. We further show that GFP+ HL-60 cells reside in close proximity to VE-cadherin- and CD31-expressing endothelial cells, suggesting that the perivascular niche may have a critical role in the maintenance and survival of LCs.

Topics: Animals; Antineoplastic Agents; Cell Movement; Cell Tracking; Diphosphates; Genes, Reporter; HL-60 Cells; Humans; Leukemia; Luminescent Measurements; Mice; Stilbenes; Transduction, Genetic; Tumor Burden; Xenograft Model Antitumor Assays

Three leukemic patients showing minimal bone uptake of Tc-99m pyrophosphate but with good uptake of methylene diphosphonate are described.

Topics: Aged; Bone and Bones; Diphosphates; Diphosphonates; Female; Humans; Leukemia; Male; Middle Aged; Radionuclide Imaging; Technetium; Technetium Tc 99m Medronate; Technetium Tc 99m Pyrophosphate

Topics: Adult; Blood-Brain Barrier; Brain Neoplasms; Diphosphates; Humans; Leukemia; Sodium Pertechnetate Tc 99m; Technetium; Technetium Tc 99m Pyrophosphate

Aminomalonic acid is a strong in vitro inhibitor of L-asparagine synthetase from Leukemia 5178Y/AR and from mouse pancreas; the agent is formally competitive with L-aspartic acid (Ki = 0.0023 M and 0.0015 M for the tumoral and pancreatic enzymes, respectively). Since aminomalonic acid is unstable and inert in vivo as an inhibitor of L-asparagine synthetase, attempts were made to deliver it to the site of its intended action via precursors: the diamide (2-aminomalonamide), the diester (diethylaminomalonate), and the keto acid (ketomalonic acid). Each of these putative 'pro drugs' was shown to be susceptible to metabolism to aminomalonate by mammalian and bacterial enzymes, in vitro. In vivo, aminomalonamide failed to inhibit tumoral L-asparagine synthetase at any time period up to 24 h after its oral or intraperitoneal administration. The diester and keto acid were similarly inactive. However, with specialized techniques it was possible to demonstrate that the diamide significantly inhibited the amidation and/or incorporation of L-aspartic acid into the L-asparaginyl residues of protein. Chemical manipulations of aminomalonic acid aimed at introducing irreversibly reacting functions are warranted.

Topics: Adenosine Triphosphate; Ammonium Chloride; Animals; Aspartate-Ammonia Ligase; Aspartic Acid; Cells, Cultured; Diphosphates; Glutamine; Kidney; Leukemia; Ligases; Liver; Malonates; Mice; Pancreas; Proteins

Topics: Adenine Nucleotides; Adenosine; Adenosine Diphosphate; Blood Platelet Disorders; Blood Platelets; Collagen; Diphosphates; Epinephrine; Hemophilia A; Humans; Leukemia; Leukemia, Myeloid; Norepinephrine; Research; Serotonin