Modification of carboplatin by Jurkat cells

Pasqua, Anthony J. Di; Goodisman, Jerry; Kerwood, Deborah J.; Toms, Bonnie B.; Dabrowiak, James C.

doi:10.1016/j.jinorgbio.2007.06.018

Cited by 10 publications

(8 citation statements)

References 11 publications

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“…31, in vitro cell proliferation assays of Jurkat cells cultured in the presence of carboplatin showed that for cell concentrations below 10 7 per mL, the rate of decay l c of carboplatin was unaffected by the presence of cells and was in fact approximately linear. In the experimental conditions relevant to our model, IGROV-1 cell numbers do not exceed 10 6 per mL.…”

Section: Assumption On Carboplatin Degradationmentioning

confidence: 99%

The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

Jain

Meyer‐Hermann

2011

Cancer Research

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Resistance to standard chemotherapy (carboplatin þ paclitaxel) is one of the leading causes of therapeutic failure in ovarian carcinomas. Emergence of chemoresistance has been shown to be mediated in part by members of the Bcl family of proteins including the antiapoptotic protein Bcl-x L , whose expression is correlated with shorter disease-free intervals in recurrent disease. ABT-737 is an example of one of the first small-molecule inhibitors of Bcl-2/Bcl-x L that has been shown to increase the sensitivity of ovarian cancer cells to carboplatin. To exploit the therapeutic potential of these two drugs and predict optimal doses and dose scheduling, it is essential to understand the molecular basis of their synergistic action. Here, we build and calibrate a mathematical model of ABT-737 and carboplatin action on an ovarian cancer cell line (IGROV-1). The model suggests that carboplatin treatment primes cells for ABT-737 therapy because of an increased dependence of cells with DNA damage on Bclx L for survival. Numerical simulations predict the existence of a threshold of Bcl-x L below which these cells are unable to recover. Furthermore, co-plus posttreatment of ABT-737 with carboplatin is predicted to be the best strategy to maximize synergism between these two drugs. A critical challenge in chemotherapy is to strike a balance between maximizing cell-kill while minimizing patient drug load. We show that the model can be used to compute minimal doses required for any desired fraction of cell kill. These results underscore the potential of the modeling work presented here as a valuable quantitative tool to aid in the translation of novel drugs such as ABT-737 from the experimental to clinical setting and highlight the need for close collaboration between modelers and experimental scientists. Cancer Res; 71(3); 705-15. Ó2010 AACR.

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Section: Assumption On Carboplatin Degradationmentioning

confidence: 99%

The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

Jain

Meyer‐Hermann

2011

Cancer Research

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“…14 The calculated value of the association constant K for the dimer is the average ± the standard deviation, i.e. K (M -1 ) = 391 ± 127. and in culture medium containing human cancer cells 18.…”

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confidence: 99%

Stability of carboplatin and oxaliplatin in their infusion solutions is due to self-association

et al. 2011

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Carboplatin and oxaliplatin are commonly used platinum anticancer agents that are sold as ready-to-use aqueous infusion solutions with shelf lives of 2 and 3 years, respectively. The observed rate constants for the hydrolysis of these drugs, however, are too large to account for their long shelf lives. We here use electrospray-trap mass spectrometry to show that carboplatin and oxaliplatin are self-associated at concentrations in their ready-to-use infusion solutions (~27 mM and 13 mM, respectively) and, as expected, when the drug concentration is reduced to more physiologically relevant concentrations (100 μM and 5 μM, respectively) the association equilibrium is shifted in favor of the monomeric forms of these drugs. Using (1)H NMR we measure the intensity of the NH resonance of the two symmetry-equivalent NH(3) molecules of carboplatin, relative to the intensity of the γ-methylene CH resonance, as a function of total drug concentration. Then, by fitting the data to models of different molecularity, we show that the association complex is a dimer with a monomer-dimer association constant of K (M(-1)) = 391 ± 127. The work presented here shows that carboplatin and oxaliplatin mainly exist as association complexes in concentrated aqueous solution, a property that accounts for the long term stability of their ready-to-use infusion solutions, and that these association complexes may exist, to some extent, in the blood after injection.

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“…This was supported by Di Pasqua's 2007 finding that carbonate-aged carboplatin is more cytotoxic to human neuroblastoma, proximal renal tube, and Namalwa-luc Burkitt's lymphoma cells than the native drug (24). It was also seen that Jurkat cells produce an unidentified extracellular substance which modifies carboplatin (25), similar to the defense mechanism against cisplatin reported by Dabrowiak and coworkers (20).…”

Section: Introductionmentioning

confidence: 58%

Influence of Carbonate on the Binding of Carboplatin to DNA

Sorokanich

Pasqua

Geier

et al. 2008

Chemistry & Biodiversity

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The reaction of aged carboplatin (reaction of carboplatin in 24 mM NaHCO 3 for 45 h, 37 o C, pH 8.6) with pBR322 DNA for 0 ≤ r ≤ 2.8, where r = [drug]/ [DNAbp], in 24 mM HEPES buffer, pH 7.4, for 24 h followed by agarose gel electrophoresis showed DNA mobility changes consistent with unwinding closed circular DNA. However, identical experiments conducted in a two buffer system, 24mM HEPES plus 24mM carbonate, showed no DNA mobility changes, indicating that carbonate blocks formation of the 1,2-intrastrand crosslink on DNA. Studies with aged carboplatin and with cisplatin carried out with 2.0 ≤ r ≤ 10.0 in the two buffer system show that some DNA binding and unwinding occurs for both drugs. Since carbonate inhibits the binding of aged carboplatin and cisplatin to DNA, carbonate present in the body likely modulates the reactivity of these drugs with a variety of biological targets including DNA.

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Modification of carboplatin by Jurkat cells

Cited by 10 publications

References 11 publications

The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

The Molecular Basis of Synergism between Carboplatin and ABT-737 Therapy Targeting Ovarian Carcinomas

Stability of carboplatin and oxaliplatin in their infusion solutions is due to self-association

Influence of Carbonate on the Binding of Carboplatin to DNA

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