Clinical significance of ABCB1 genotyping in oncology.

BACKGROUND: P-glycoprotein (Pgp) is a drug efflux pump that transports natural products, including taxanes and other chemotherapeutic agents, from cells. Several frequent polymorphisms in ATP binding cassette gene B1 (ABCB1) may influence Pgp levels and drug efflux. The purpose of this review was to assess the clinical significance of ABCB1 polymorphisms in oncology. METHODS: Peer-reviewed studies were identified through a search of PubMed/MEDLINE (1990-2008) and the ASCO abstracts (2003-2008) database. Included studies described clinical trials where ABCB1 genotyping was performed in patients with cancer. Search terms included ABCB1, Pgp, docetaxel, paclitaxel, irinotecan, imatinib, and anticancer agent. Studies were excluded if the manuscript was not available in English. RESULTS: The influence of polymorphisms in ABCB1 2677G>T/A, 3435C>T, and 1236C>T and progression-free and overall survival in 309 patients from the Australian Ovarian Cancer Study treated with paclitaxel/carboplatin demonstrated that compared to homozygote GG carriers at 2677, women with the minor T/A alleles were significantly less likely to relapse following treatment. Other trials of ABCB1 genotyping in breast and prostate cancer patients receiving taxanes have shown inconsistent results. Pharmacokinetic studies where ABCB1 was genotyped and patients received irinotecan or imatinib have also shown inconsistent results. CONCLUSION: A number of commercially available drugs are substrates for Pgp, and the ABCB1-variant genotypes are frequent and functionally significant, which may have future implications for drug dosing.

Docetaxel and irinotecan in recurrent or metastatic head and neck cancer: a phase 2 trial of the Eastern Cooperative Oncology Group.

BACKGROUND: Docetaxel and irinotecan have single-agent antitumor activity in squamous cell carcinoma of the head and neck (SCCHN). The authors sought to evaluate their combination in the treatment of patients with recurrent or metastatic SCCHN. METHODS: Eligibility criteria included recurrent or metastatic SCCHN with measurable disease, good performance status, and adequate laboratory parameters. Patients received docetaxel 35 mg/m(2) and irinotecan 60 mg/m(2), intravenously, on Days 1 and 8, every 21 days, until disease progression. The authors assessed UGT1A1 genotype, vascular endothelial growth factor (VEGF) in serum, and cyclooxygenase-2 and VEGF in baseline tumor tissue. RESULTS: Fifty-two patients were analyzable: 20 chemotherapy naive (Group A) and 32 previously treated with 1 chemotherapy regimen (Group B); 73% of patients had distant metastasis, and 60% were paclitaxel-exposed. In Group A, 3 (15%) patients achieved a partial response; in Group B, 1 (3%) patient achieved a partial response. Median progression-free survival (PFS) and overall survival were 3.3 and 8.2 months in Group A and 1.9 and 5.0 months in Group B, respectively. Common serious toxicities were diarrhea, fatigue, and anorexia. Patients with high serum VEGF had a median PFS of 2.8 months versus 1.7 months for patients with low VEGF (P = .085). CONCLUSIONS: Docetaxel and irinotecan had acceptable toxicities, but efficacy results in unselected patients with recurrent or metastatic SCCHN did not suggest an advantage over docetaxel alone or platinum-based regimens.

Evaluation of mRNA by Q-RTPCR and protein expression by AQUA of the M2 subunit of ribonucleotide reductase (RRM2) in human tumors.

PURPOSE: The purpose of this study was to evaluate baseline RRM2 protein and gene expression in tumors of patients receiving 3-AP. METHODS: Tumor blocks from patients enrolled in phase I and II clinical studies using 3-AP, were evaluated for RRM2 gene and protein expression by quantitative real time polymerase chain reaction (Q-RTPCR) and automated quantitative analysis (AQUA). RESULTS: Esophageal and gastric cancers overexpressed RRM2 protein when compared to prostate cancer (Z-score, 0.68 +/- 0.94 SD, vs 0.41 +/- 0.84 SD, respectively; p = 0.04). Esophageal and gastric cancers also overexpressed RRM2 mRNA when compared to prostate cancer (relative gene expression 2.56 +/- 1.49 SD, vs 0.29 +/- 0.20 SD, respectively; p = 0.02). Protein and gene expression were moderately associated (Spearman's rank correlation = 0.30; p = 0.12). CONCLUSION: RRM2 gene and protein expression varies by tumor type.

Pharmacogenetics and irinotecan therapy.

PURPOSE: Irinotecan metabolism, irinotecan pharmacogenetic research, and the role of genetic testing before administration of the drug are reviewed. SUMMARY: Irinotecan is approved worldwide for the treatment of metastatic colorectal cancer but causes dose-limiting neutropenia and diarrhea. When severe, these can lead to dehydration, infection, patient discomfort, additional medication requirements, hospitalization, and death. The identification of predictive markers in irinotecan therapy has been a significant goal of pharmacogenetic research. The labeling of irinotecan was recently changed and now includes a warning of greater neutropenia risk in patients with reduced activity in the drug-metabolizing enzyme uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1). A known marker of reduced UGT1A1 activity is the genetic variant UGT1A1*28. Numerous studies have demonstrated the effects of genetic factors, especially UGT1A1*28, that contribute to interpatient variability in irinotecan pharmacokinetics and toxicity. Irinotecan's new labeling recommends that clinicians consider reducing the dosage of irinotecan in patients homozygous for UGT1A1*28. CONCLUSION: At least part of the interpatient variability of irinotecan toxicity can be explained by the UGT1A1*28 polymorphism. Patients who are homozygous for the UGT1A1*28 allele have an increased risk of developing severe neutropenia when receiving irinotecan, especially the 300-350- mg/m2 regimen. A molecular assay is now available to identify the at-risk subgroup and should be used by health care professionals to help guide irinotecan-treatment decisions.

Azacitidine: a novel agent for myelodysplastic syndromes.

PURPOSE: The pharmacology, pharmacokinetics, clinical efficacy, dosage and administration, and safety of azacitidine are reviewed. SUMMARY: Azacitidine is the first drug in a new class of compounds, known as DNA hypomethylating agents, to receive FDA-approved labeling for the treatment of myelodysplastic syndromes. It exerts its antineoplastic activity by causing a direct cytotoxic effect on abnormally proliferating hematopoietic cell lines by interfering with nucleic acid metabolism. Azacitidine is rapidly absorbed following subcutaneous injection, with peak plasma concentrations achieved within 30 minutes of administration. Based on promising results in Phase I-II testing, azacitidine entered Phase III testing in all subtypes of myelodysplastic syndromes. Azacitidine was compared with best supportive care, the previous standard therapy for myelodysplastic syndromes, demonstrating improvements in hematologic response, delaying time to progression to acute myelogenous leukemia, and increasing overall survival. Azacitidine is available as sterile lyophilized powder in single-use vials for reconstitution. The recommended dosage of azacitidine for the first treatment cycle is 75 mg/m(2) daily for seven days. The treatment cycle should be repeated every four weeks for a minimum of four cycles. Overall, azacitidine appears to be well tolerated, with the most common adverse effects being myelosuppression, nausea, and vomiting. CONCLUSION: Azacitidine is the first DNA hypomethylating agent approved by FDA for the treatment of myelodysplastic syndromes and has demonstrated superior efficacy and improvements in patients' quality of life and bone marrow function over supportive care.