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Motexafin Gadolinium and Doxorubicin in Treating Patients With Advanced Cancer

ABSTRACT: RATIONALE: Drugs used in chemotherapy use different ways to stop tumor cells from dividing so they stop growing or die. Motexafin gadolinium may increase the effectiveness of doxorubicin by making tumor cells more sensitive to the drug. PURPOSE: Phase I trial to study the effectiveness of combining motexafin gadolinium with doxorubicin in treating patients who have recurrent or metastatic cancer.

DISEASE(S): Extramedullary Plasmacytoma,Myeloproliferative Disorders,Lung Cancer,Myelodysplastic-myeloproliferative Diseases,Leukemia,Colorectal Cancer,Multiple Myeloma And Plasma Cell Neoplasm,Myelodysplastic/myeloproliferative Diseases,Small Intestine Cancer,Head And Neck Neoplasms,Angioimmunoblastic T-cell Lymphoma,Breast Neoplasms,Lymphoma,Lung Neoplasms,Breast Cancer,Unspecified Adult Solid Tumor, Protocol Specific,Prostatic Neoplasms,Prostate Cancer,Head And Neck Cancer,Plasmacytoma,Intestinal Neoplasms,Neoplasms, Plasma Cell,Multiple Myeloma,Chronic Myeloproliferative Disorders

PROVIDER: 2007594 | ecrin-mdr-crc |

REPOSITORIES: ECRIN MDR

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Project description:Objective: To assess the role of aldoketoreductases and other doxorubicin pharmacokinetic or pharmacogenomic genes in doxorubicin cytotoxicity, resistance, DNA binding activity, and subcellular localization, Methods: We conducted a whole genome microarray study to identify differences in between doxorubicin-sensitive MCF-7cc cells and doxorubicin-resistant MCF-7Dox2-12 cells in terms of their expression of genes related to doxorubicin pharmacokinetics or pharmacodynamics. Targets were then validated by pharmacologic inhibition in conjunction with drug metabolite profiling, drug localization, drug cytotoxicity, and drug DNA binding studies. Results: 2063 differentially expressed transcripts were identified, including 17% and 43% of genes or gene families associated with doxorubicin pharmacokinetics or pharmacodynamics (p values of significance of 0.05 and <0.0001, respectively). The largest changes in the expression of genes associated with doxorubicin pharmacokinetics and pharmacodynamics were chiefly among the aldo-keto reductases (AKRs) Akr1c2, Akr1c3 and Akr1b10 which convert doxorubicin to doxorubicinol. We observed that doxorubicinol exhibits dramatically reduced drug toxicity, reduced drug DNA-binding activity, and altered drug subcellular localization to lysosomes. Pharmacologic inhibition of these AKRs in MCF-7Dox2-12 cells restored drug cytotoxicity, and drug localization to the nucleus. Conclusion: These findings demonstrate the utility of using curated pharmacokinetic and pharmacodynamic knowledgebases to identify highly relevant genes associated with doxorubicin resistance. The products of one or more of these genes could effectively be shown to alter the drug’s properties, while inhibiting them restored drug DNA binding, cytotoxicity, and subcellular localization. Doxorubicin resistant cell lines of breast MCF-7 cells were generated for gene expression profilling. Two colour microarray of Agilent whole human genome nucleotide arrays was conducted with four labelling replicates of both forward and reverse labellings plus another set of 8 arrays with forward labelling. Sixteen arrays were used for this experiments. The co-cultured control cells MCF-7cc12 was generated by parallel selection process in the absence of drug.

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Motexafin Gadolinium and Doxorubicin in Treating Patients With Advanced Cancer

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