Results of NCI-sponsored phase I trials with carboplatin

Foster, Brenda J.; Clagett-Carr, K; Leyland‐Jones, Brian; Hoth, Daniel F.

doi:10.1016/0305-7372(85)90017-9

Cited by 86 publications

(41 citation statements)

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“…Gallium nitrate, a group IIIa metal salt with antineoplastic activity (1), is currently undergoing evaluation as a chemotherapeutic agent. A number of clinical studies have shown gallium to be effective in the treatment of lymphoma and bladder cancer (2)(3)(4).…”

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confidence: 99%

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

Chitambar

Wereley

1997

Journal of Biological Chemistry

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The mechanism of drug resistance to gallium nitrate is not known. Since gallium can be incorporated into ferritin, an iron storage protein that protects cells from iron toxicity, we investigated whether ferritin expression was altered in gallium-resistant (R) CCRF-CEM cells. We found that the ferritin content of R cells was decreased, while heavy chain ferritin mRNA levels and iron regulatory protein-1 (IRP-1) RNA binding activity were increased. IRP-1 protein levels were similar in gallium-sensitive (S) and R cells, indicating that R cells contain a greater proportion of IRP-1 in a high affinity mRNA binding state. 59 Fe uptake and transferrin receptor expression were decreased in R cells. In both S and R cells, gallium inhibited cellular 59 Fe uptake, increased ferritin mRNA and protein, and decreased IRP-1 binding activity. Gallium uptake by R cells was markedly diminished; however, the sensitivity of R cells to gallium could be restored by increasing their uptake of gallium with excess transferrin. Our results suggest that R cells have developed resistance to gallium by down-regulating their uptake of gallium. In parallel, iron uptake by R cells is also decreased, leading to changes in iron homeostasis. Furthermore, since gallium has divergent effects on iron uptake and ferritin synthesis, its action may also include a direct effect on ferritin mRNA induction and IRP-1 activity.Gallium nitrate, a group IIIa metal salt with antineoplastic activity (1), is currently undergoing evaluation as a chemotherapeutic agent. A number of clinical studies have shown gallium to be effective in the treatment of lymphoma and bladder cancer (2-4). Although gallium is in clinical use, information regarding its action at the cellular and molecular levels is largely incomplete. It has been known for some time that gallium resembles iron in certain respects. Gallium binds avidly to the iron transport protein Tf 1 (5) and is incorporated into cells by Tf receptor-dependent and -independent transport systems (6 -8). Furthermore, we have shown that gallium inhibits the growth of several leukemic cell lines by inhibiting cellular iron uptake and by blocking the activity of ribonucleotide reductase (9 -11).Iron taken up by cells is stored in ferritin, a high molecular weight protein composed of 24 subunits of H and L chains (12). Ferritin sequesters excess intracellular iron and protects cells from the toxicity of iron overload. An increase in the delivery of iron to cells therefore serves as a powerful stimulus for ferritin synthesis. It is now established that iron-dependent ferritin and transferrin receptor gene expression is regulated by the binding of two iron regulatory proteins (IRPs), IRP-1 and IRP-2, to sequences termed iron-responsive elements (IREs) present at the 5Ј-untranslated region of ferritin mRNA and the 3Ј-untranslated region of Tf receptor mRNA (13-17). In irondepleted cells, IRPs bind with high affinity to the IREs, resulting in suppression of ferritin mRNA translation and stabilization of Tf receptor mRNA (incr...

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Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

Chitambar

Wereley

1997

Journal of Biological Chemistry

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“…Myelosuppression continues to be the dose-limiting toxicity of many antineoplastic agents, including carboplatin [1]. While neutropenia may be diminished with recombinant human G-CSF (rHuG-CSF), thrombocytopenia is often treated clinically by platelet transfusion.…”

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The Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large‐Animal Model of Chemotherapy‐Induced Thrombocytopenia

et al. 2000

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“…2,3 In particular, it entered the clinic in the 1970s as a treatment for ovarian carcinoma but difficulties were encountered, as it is insoluble in water and is thus difficult to formulate. However, it has recently been recognised [4][5][6] as a second-line treatment for ovarian carcinoma.…”

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“…It is oxidatively metabolised 7,8 in the liver to the N-hydroxymethyl analogue 2. This carbinolamine decomposes to give the N-desmethyl analogue, pentamethylmelamine 3a, which also has antitumour activity 3 and is slightly soluble in water. Of considerably greater aqueous solubility is 2,4,6-tris(N-hydroxymethyl-N-methylamino)-1,3,5-triazine 4 (trimelamol), which also shows therapeutic activity, 9 however, the chemical instability of 4 precluded its routine use in the clinic.…”

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Labelled compounds of interest as antitumour agents – VIII. Synthesis of ²H‐isotopomers of pentamethylmelamine and of a potential prodrug thereof

Ferrer

Naughton

Threadgill

2002

Labelled Comp Radiopharmac

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Treatment of 2‐chloro‐4,6‐(dimethylamino)‐1,3,5‐triazine with trideuteromethylamine gave 4,6‐(dimethylamino)‐2‐trideuteromethyl‐1,3,5‐triazine, an isotopomer of the experimental anticancer agent pentamethylmelamine (PMM). Mitsunobu coupling with 1,2‐dimethyl‐3‐hydroxymethyl‐5‐methoxy‐indole‐4,7‐dione gave 1,2‐dimethyl‐3‐(N‐(4,6‐bis(dimethylamino)‐1,3,5‐triazin‐2‐yl)‐N‐trideuteromethylaminomethyl)‐5‐methoxyindole‐4,7‐dione. This conjugate is a potential reductively triggered prodrug of PMM. Copyright © 2002 John Wiley & Sons, Ltd.

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Results of NCI-sponsored phase I trials with carboplatin

Cited by 86 publications

References 4 publications

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

The Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large‐Animal Model of Chemotherapy‐Induced Thrombocytopenia

Labelled compounds of interest as antitumour agents – VIII. Synthesis of ²H‐isotopomers of pentamethylmelamine and of a potential prodrug thereof

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Results of NCI-sponsored phase I trials with carboplatin

Cited by 86 publications

References 4 publications

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

Resistance to the Antitumor Agent Gallium Nitrate in Human Leukemic Cells Is Associated with Decreased Gallium/Iron Uptake, Increased Activity of Iron Regulatory Protein-1, and Decreased Ferritin Production

The Pharmacokinetics and Pharmacodynamics of GW395058, a Peptide Agonist of the Thrombopoietin Receptor, in the Dog, a Large‐Animal Model of Chemotherapy‐Induced Thrombocytopenia

Labelled compounds of interest as antitumour agents – VIII. Synthesis of 2H‐isotopomers of pentamethylmelamine and of a potential prodrug thereof

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Labelled compounds of interest as antitumour agents – VIII. Synthesis of ²H‐isotopomers of pentamethylmelamine and of a potential prodrug thereof