ABSTRACT
BACKGROUND: The epidermal growth factor receptor (EGFR) is expressed in ovarian cancer, but agents targeting this pathway have shown little effect as single agents. This may be due to the presence of alternative pathways, particularly activation of the PI3K/Akt/MTOR pathway. METHODS: We have therefore examined the effect of inhibitors of this pathway (ZSTK474 and sirolimus) in combination with the EGFR inhibitors erlotinib and gefitinib in ovarian cancer primary cell cultures. RESULTS: The single-agent EGFR inhibitors showed little activity, although some activity was seen with the single-agent PI3K inhibitor, ZSTK474. Combinations of ZSTK474 with EGFR inhibitors showed enhanced activity with some evidence of synergy, whereas sirolimus combinations were less active. The results were not explicable on the basis of PIK3CA mutation or amplification, or PTEN loss, although one tumour with a KRAS mutation showed resistance to EGFR inhibitors. However, there was correlation of the EGFR expression with sensitivity to EGFR and resistance to PI3K active agents, and inverse correlation in the sensitivity of individual tumours to agents active against these pathways, suggesting a mechanism of action for the combination. CONCLUSION: Phase I/II clinical trials with these agents should include further pharmacodynamic endpoints and molecular characterisation to identify patients most likely to benefit from this strategy.
Subject(s)
ErbB Receptors/antagonists & inhibitors , Ovarian Neoplasms/drug therapy , Phosphoinositide-3 Kinase Inhibitors , Sirolimus/pharmacology , Triazines/pharmacology , Antibiotics, Antineoplastic/pharmacology , Cell Proliferation/drug effects , Drug Synergism , ErbB Receptors/genetics , ErbB Receptors/metabolism , Erlotinib Hydrochloride , Female , Gefitinib , Humans , Ovarian Neoplasms/metabolism , Phosphatidylinositol 3-Kinases/metabolism , Protein Kinase Inhibitors/pharmacology , Quinazolines/pharmacology , Tumor Cells, CulturedABSTRACT
Oligodendrogliomas may be divided into those with deletion of chromosomes 1p and 19q (Del+), and those without (Del-). Del+ tumours show better survival and chemoresponsiveness but the reason for this difference is unknown. We have investigated whether these subgroups differ in (a) apoptotic index, (b) the proportion of cells licensed for DNA replication but not in-cycle, and (c) the relative length of G1-phase. Fluorescence in situ hybridisation with probes to 1p and 19q was used to determine the deletion status of 54 oligodendrogliomas, including WHO grades II and III. The apoptotic index was determined using counts of apoptotic bodies. Replication-licensed non-proliferating cells were determined from the Mcm2 minus Ki67 labelling index, whilst the geminin to Ki67 ratio was used as a measure of the relative length of G1. Del+ oligodendrogliomas showed a higher apoptotic index than Del- tumours (P=0.037); this was not accounted for by differences in tumour grade or in proliferation. There were no differences in the Mcm2-Ki67 index or in the geminin/Ki67 ratio between the subgroups, but grade III tumours showed a higher proportion of licensed non-proliferating cells than grade II tumours (P=0.001). An increased susceptibility to apoptosis in oligodendrogliomas with 1p+/-19q deletion may be important in their improved clinical outcome compared to Del- tumours.
Subject(s)
Apoptosis/physiology , Cell Proliferation , Chromosome Deletion , Chromosomes, Human, Pair 1/genetics , Oligodendroglioma/genetics , Adult , Apoptosis/genetics , Cell Survival , Cytogenetics/methods , DNA Replication , Female , Humans , In Situ Hybridization, Fluorescence/methods , Ki-67 Antigen/metabolism , Male , Middle Aged , Oligodendroglioma/classification , Retrospective StudiesABSTRACT
A case is reported of a 35-year-old woman who underwent a chorion villus biopsy (CVB) at 17 weeks' gestation after intrauterine growth retardation and oligohydramnios were diagnosed by ultrasound scan. Chromosome analysis of the CVB direct preparations showed a 47,XX,+6 karyotype in all cells. The pregnancy was terminated and subsequent analysis of cultured cells from both the CVB and the post-mortem placenta showed three cell lines: 46,XX, 47,XX,+6 and 69,XXX, while fetal skin and muscle were entirely 69,XXX. An explanation is proposed for the origin and distribution of the three cell lines.
Subject(s)
Chorionic Villi Sampling , Chromosome Aberrations/diagnosis , Ploidies , Trisomy , Adult , Cells, Cultured , Chromosome Disorders , Chromosome Mapping , DNA/analysis , Female , Fetal Growth Retardation/diagnostic imaging , Fetal Growth Retardation/genetics , Humans , Karyotyping , Male , Mosaicism , Oligohydramnios/diagnostic imaging , Pregnancy , Pregnancy Trimester, Second , Ultrasonography, PrenatalABSTRACT
A 2 year old female presenting with bilateral sporadic aniridia was found to have an apparently balanced reciprocal translocation with a chromosome 11 breakpoint within band p13. Fluorescence in situ hybridisation (FISH) studies with distal 11p13 specific cosmids showed that the chromosome 11 breakpoint lay between the aniridia (PAX6) locus and a region approximately 100 kb distal to PAX6 defined by the cosmid FO2121. Although this patient did not have a detectable deletion within PAX6, her aniridia may have resulted from a disruption of the distal chromatin domain containing either enhancers or regulators for PAX6. This case may therefore be another example of aniridia caused by a position effect as recently described in two familial aniridia patients in which the phenotype cosegregated with chromosome abnormalities with 11p13 breakpoints.