ABSTRACT
BACKGROUND: The p53 codon 72 polymorphism, which results in either an arginine or proline residue, plays a different role in vitro and in vivo in cell survival and drug resistance. We verified, in vitro, the impact of the arginine allele on cell survival under normoxia and hypoxia, and investigated in vivo the role of p53 codon 72 arginine homozygosity in the clinical outcome of advanced breast cancer patients. METHODS: Tumors at advanced stages grow in vivo in a hypoxic environment, and we mimicked such conditions in vitro using p53 null breast cancer cells transfected with either the arginine or proline allele. We also analyzed in vivo the p53 codon 72 genotype status of advanced breast cancer patients. RESULTS: In vitro transfection of the arginine allele induced higher cell death under normoxia, whereas cell death was greater in proline-transfected cells under hypoxia. The arginine allele upregulated BCRP-I, a hypoxia response gene, which increases drug resistance. Metastatic breast cancer patients homozygous for arginine had a significantly shorter time to progression and overall survival than those with heterozygous arginine/proline tumors. CONCLUSION: We provide a molecular explanation for the association of the arginine allele with tumor aggressiveness and treatment resistance in advanced breast cancer.
Subject(s)
Alleles , Arginine/genetics , Breast Neoplasms/genetics , Codon/genetics , Polymorphism, Single Nucleotide/genetics , Tumor Suppressor Protein p53/genetics , ATP Binding Cassette Transporter, Subfamily G, Member 2 , ATP-Binding Cassette Transporters/genetics , Adult , Aged , Breast Neoplasms/pathology , Breast Neoplasms/physiopathology , Cell Line, Tumor , Cell Survival/physiology , Disease Progression , Drug Resistance, Neoplasm/genetics , Female , Humans , Hypoxia/physiopathology , Kaplan-Meier Estimate , Middle Aged , Neoplasm Proteins/genetics , Proline/genetics , Transfection , Up-RegulationABSTRACT
OBJECTIVE: Taxanes and fluoropyrimidines are active in metastatic breast cancer (MBC), and their combination has proven effective in anthracycline-refractory patients. We conducted a phase I study to determine the maximum tolerated dose (MTD) of uracil plus tegafur (UFT) given in combination with leucovorin (LV) and paclitaxel (Pacl) in patients with refractory MBC. METHODS: Pacl was infused at a fixed dose of 150 mg/m2 on day 1. UFT, at doses escalated by 50 mg/m2 starting from 200 mg/m2 . day, and LV, at a fixed dose of 90 mg/day, were given orally every 8 h for 11 days (days 3-13). Cohorts of at least 3 patients were treated at each dose level, and if 1 experienced dose-limiting toxicity (DLT), a maximum of 3 additional patients were added at the same dose level. MTD was reached if 2 out of the 6 patients experienced DLT. RESULTS: Sixteen patients were enrolled in the study. The most important toxicity observed was hematological. Nonhematological toxicities were paresthesia and myalgia, asthenia, nausea, and mucositis. DLT occurred in only 1 patient (grade 3 hepatic toxicity). CONCLUSIONS: The recommended dose for a subsequent phase II trial is Pacl 150 mg/m2 on day 1, and UFT 300 mg/m2 and LV 90 mg on days 3-13, every 2 weeks.
Subject(s)
Antineoplastic Combined Chemotherapy Protocols/adverse effects , Breast Neoplasms/drug therapy , Adult , Aged , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Breast Neoplasms/pathology , Cell Line, Tumor , Drug Administration Schedule , Drug Screening Assays, Antitumor , Female , Humans , Leucovorin/administration & dosage , Maximum Tolerated Dose , Middle Aged , Models, Theoretical , Neoplasm Metastasis , Paclitaxel/administration & dosage , Tegafur/administration & dosage , Uracil/administration & dosageABSTRACT
We report the stopping power of molecular hydrogen for antiprotons of kinetic energy above the maximum (approximately 100 keV) with the purpose of comparing with the proton one. Our result is consistent with a positive difference in antiproton-proton stopping powers above approximately 250 keV and with a maximum difference between the stopping powers of 21%+/-3% at around 600 keV.
