pyrophosphate and Melanoma

Vascular disrupting agents (VDA) cause acute shutdown of abnormal established tumor vasculature, followed by massive intratumoral hypoxia and necrosis. However, a viable rim of tumor tissue invariably remains from which tumor regrowth rapidly resumes. We have recently shown that an acute systemic mobilization and homing of bone marrow-derived circulating endothelial precursor (CEP) cells could promote tumor regrowth following treatment with either a VDA or certain chemotherapy drugs. The molecular mediators of this systemic reactive host process are unknown. Here, we show that following treatment of mice with OXi-4503, a second-generation potent prodrug derivative of combretastatin-A4 phosphate, rapid increases in circulating plasma vascular endothelial growth factor, stromal derived factor-1 (SDF-1), and granulocyte colony-stimulating factor (G-CSF) levels are detected. With the aim of determining whether G-CSF is involved in VDA-induced CEP mobilization, mutant G-CSF-R(-/-) mice were treated with OXi-4503. We found that as opposed to wild-type controls, G-CSF-R(-/-) mice failed to mobilize CEPs or show induction of SDF-1 plasma levels. Furthermore, Lewis lung carcinomas grown in such mice treated with OXi-4503 showed greater levels of necrosis compared with tumors treated in wild-type mice. Evidence for rapid elevations in circulating plasma G-CSF, vascular endothelial growth factor, and SDF-1 were also observed in patients with VDA (combretastatin-A4 phosphate)-treated cancer. These results highlight the possible effect of drug-induced G-CSF on tumor regrowth following certain cytotoxic drug therapies, in this case using a VDA, and hence G-CSF as a possible therapeutic target.

Topics: Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Bevacizumab; Chemokine CXCL12; Diphosphates; Endothelial Cells; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Humans; Melanoma; Mice; Mice, Inbred C57BL; Mice, Nude; Mice, Transgenic; Neoplasms; Prodrugs; Stem Cells; Stilbenes; Vascular Endothelial Growth Factor A; Xenograft Model Antitumor Assays

A strategy to develop water soluble, biocompatible nanocomposite probe for the detection of pyrophosphate (PPi) in physiological conditions and in in vitro live melanoma cancer cells (B16F10) is reported. The self-assembled nanocomposite probe comprised of amino acid (histidine) functionalized perylenediimide (PDI-HIS), copper ion and graphene oxide (GO) and that could be utilized as a highly effective sensing platform in biological conditions and cellular environment via fluorescence "turn-on" for PPi detection. This controlled fabrication of metal organic self-assembled spheres along with GO proved very valuable for the detection of PPi in unprecedented sensitivity over other competing ions. The PDI-HIS-Cu-GO (PCG) nanocomposite sensor provides a unique platform for the fluorogenic detection of PPi having a very low limit of detection (LOD) of 0.60×10

Topics: Animals; Cell Line, Tumor; Copper; Diphosphates; Graphite; Histidine; Imides; Melanoma; Mice; Nanostructures; Optical Imaging; Oxides; Perylene; Solubility; Spectrometry, Fluorescence; Water

To evaluate whether nuclear activity as measured by the disodium phosphate 32P (32P) uptake test for uveal melanoma is of prognostic value and corresponds to known prognostic factors.. A retrospective analysis of 121 patients with choroidal and/or ciliary body melanoma, tested with the 32P uptake test before enucleation between January 1, 1973, and December 31, 1976, at the Leiden University Medical Center. We obtained the 25-year follow-up information of this group of patients and compared the 32P test results and histopathological variables with the long-term survival rates.. The cumulative 5-, 10-, and 20-year survival for melanoma-related death was 81.4%, 73.3%, and 63.9%, respectively. The results of the 32P uptake test were not significantly correlated with survival (P =.35). Of all prognostic factors under study, tumor diameter, cell type, and mitotic count were identified as the most important prognostic markers for uveal melanoma in this group.. The 32P isotope uptake test has no prognostic value for uveal melanoma. Moreover, the results of this study indicate that it is unlikely that cell activity as determined by 32P uptake involves mitotic activity of the tumor.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Diphosphates; Eye Enucleation; Female; Humans; Male; Melanoma; Middle Aged; Phosphorus Radioisotopes; Prognosis; Retrospective Studies; Survival Rate; Uveal Neoplasms

Two partially purified fractions of the ethanol precipitate (70-95%) of the water extract of Harding-Passey mouse melanoma, which inhibit protein and DNA syntheses of B-16 melanoma cells in culture, also inhibit protein synthesis in various cell-free systems. By examining their inhibitory effects on limited reactions of protein synthesis, it was found that one of them (ME II) inhibits protein synthesis by blocking aminoacyl-tRNA formation, while the other (ME IV) does not. This inhibition of aminoacyl-tRNA formation was not limited to specific amino acids. Since the amino acid-dependent pyrophosphate (PPi)-ATP exchange reaction catalyzed by aminoacyl-tRNA synthetases was not inhibited, it was concluded that some factor(s) in ME II inhibits amino acid transfer from aminoacyl-AMP to tRNA. ME II contains more than 20 proteins from 10,000 to 90,000 daltons. EDTA treatment of this fraction caused the release of low-molecular substances with inhibitory activity from the proteins. The molecular weights of the active substances are less than 5,000 daltons. The active low-molecular substances are apparently not peptides or nucleotides.

Topics: Adenosine Triphosphate; Amino Acids; Amino Acyl-tRNA Synthetases; Animals; Cell Line; Cell-Free System; Diphosphates; In Vitro Techniques; Melanoma; Mice; Molecular Weight; Peptide Elongation Factors; Protein Biosynthesis; Proteins; Rats; RNA, Transfer, Amino Acyl; Tissue Extracts

Topics: Copper; Diagnosis, Differential; Diphosphates; Humans; Melanoma; Phosphorus Radioisotopes; Skin Neoplasms

Bone-to-bone, iliosacral joint-to-os sacrum and joint-to-joint ratios were computed using the region-of-interest technique 2 to 3 hrs. after injection of 99mTc Sn-methylene-diphosphonate or 99mTc Sn-pyrophosphate in 139 patients with skeletal diseases (bone tumours, degenerative changes of the spine and joints, inflammatory changes of joints) as well as in 123 patients with normal skeletal states. In the latter group, iliosacral joint-to-os sacrum ratios decreased with increasing age of the patients. In patients with osseous metastases of the spine ratios of 0.80 to 4.0 occurred ( reference area second vertebra below or above the affected vertebra). In degenerative changes of the spine values of 0.80 to 1.69 were computed. These results show, that 74% of the spine metastases could not be differentiated from benign changes of the spine by determining their relative amounts of bone uptake. In bone tumours of the extremities and in rheumatoid or gouty arthritis of the small joints (hands and feet) the highest ratios, i.e. contrasts, occurred referring to a contralateral reference area. Osteoarthritic and inflammatory alterations of the big joints could not be differentiated because of percentual distribution of the increased joint-to-joint ratios turned out to be nearly identical.

Topics: Adult; Aged; Arthritis; Arthritis, Rheumatoid; Bone Diseases; Bone Neoplasms; Colonic Neoplasms; Diphosphates; Diphosphonates; Extremities; Femur; Gout; Hemangiosarcoma; Humans; Hypertrophy; Lumbar Vertebrae; Melanoma; Middle Aged; Neoplasm Metastasis; Osteoarthritis; Radionuclide Imaging; Spinal Neoplasms; Spinal Osteophytosis; Spondylolisthesis; Technetium

A positive 99mTc-pyrophosphate bone scan is reported in a proven case of large compact bone island. Pyrophosphate uptake in this case is presumed to be due to either large size or growth of the bone island. A radionuclide bone scan does not always differentiate bone islands from metastatic or inflammatory sclerotic bone lesions.

Topics: Adult; Bone Neoplasms; Diagnosis, Differential; Diphosphates; Humans; Male; Melanoma; Neoplasm Metastasis; Radionuclide Imaging; Technetium

A retrospective study of 795 consecutive bone scans employing either 18F or 99mTc-pyrophosphate to evaluate the diagnostic value of renal asymmetry in such scans has been carried out. It is concluded that asymmetric renal images in bone scans convey relatively specific information regarding renal pathology, especially in the 99mTc-pyrophosphate studies.

Topics: Adenocarcinoma; Adult; Aged; Bone Neoplasms; Carcinoma, Bronchogenic; Diphosphates; Female; Fluorine; Humans; Kidney; Kidney Diseases; Kidney Neoplasms; Male; Melanoma; Radioisotopes; Radionuclide Imaging; Retrospective Studies; Technetium; Ureteral Obstruction

Topics: Animals; Bone and Bones; Bone Neoplasms; Breast Neoplasms; Carcinoma; Diphosphates; Humans; Lung Neoplasms; Male; Melanoma; Neoplasm Metastasis; Prostatic Neoplasms; Radionuclide Imaging; Rectal Neoplasms; Sodium; Technetium; Time Factors; Urinary Bladder Neoplasms