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- Green, Henrik, 1975-
(författare)
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Pharmacogenetic Studies of Paclitaxel in Ovarian Cancer : focus on interindividual differences in pharmacodynamics and pharmacokinetics
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Ovarian cancer is one of the most common female cancer diseases in the world today and in Sweden more than 800 new cases are diagnosed every year. The standard treatment consists of chemotherapy with paclitaxel in combination with carboplatin after initial cytoreductive surgery. The response to treatment and the severity of adverse drug reactions after chemotherapy varies greatly among individuals, and one of the most important factors responsible for these differences is now recognized to be the genetic variability. One of the major obstacles to successful treatment is drug resistance. Several potential mechanisms have been suggested for the resistance to paclitaxel, such as mutations in the target protein β-tubulin, single nucleotide polymorphisms (SNPs) in the gene ABCB1, which encodes the transport protein P-glycoprotein. P-glycoprotein can mediate efflux of various drugs from cancer cells as well as from the circulation into the intestinal lumen, and overexpression and/or high activity leads to drug resistance and/or increased elimination. Another reason might be the high interindividual variability of paclitaxel plasma concentrations, which has been suggested to be influenced by variability in metabolic enzymes, such as CYP2C8 and CYP3A4, and transport proteins e.g. P-glycoprotein.In the studies constituting this thesis we have investigated the possibilities of predicting the pharmacokinetics of paclitaxel as well as the tumor response and adverse drug reactions after chemotherapy in the preparation of personalized chemotherapy. We studied the correlation between the response and the presence of mutations in the dominant β-tubulin gene and SNPs in ABCB1. DNA from 40 ovarian tumors was screened for sequence variations in the β-tubulin gene without finding any, showing that β-tubulin mutations are rare and unlikely to be a clinically relevant resistance mechanism for paclitaxel. The SNPs G2677T/A and C3435T in the ABCB1 gene were determined in 53 ovarian cancer tumors from patients with poor (progressive disease or relapse within one year) or good (disease-free survival of more than one year) response to paclitaxel-carboplatin chemotherapy. Patients homozygously mutated for G2677T/A had a higher probability of responding to chemotherapy. There was also a dose-dependent influence of the number of mutated alleles on the response to paclitaxel treatment. No correlation was found for the C3435T variant.By using a newly developed quantitative LC/MS method for the simultaneous determination of paclitaxel and its hydroxymetabolites in human plasma we assessed the individual elimination of paclitaxel in 33 ovarian cancer patients. The patients were genotyped for SNPs in the ABCB1, CYP2C8 and CYP3A4 genes and their in vivo CYP3A4 enzyme activity, tumor response and toxicity, especially the neurotoxicity, were determined. Patients heterozygous for G/A in position 2677 in ABCB1 had a significantly higher clearance of paclitaxel than patients with the wild type or homozygously mutated, but not compared to patients carrying the G/T alleles. A lower clearance of paclitaxel was also found for patients heterozygous for CYP2C8*3 when stratified according to the ABCB1 G2677T/A genotype. The CYP3A4 enzyme activity in vivo affected the relative influence of CYP2C8 and CYP3A4 on the metabolism, but not the total clearance of paclitaxel. The exposure to paclitaxel was correlated to the neurotoxicity, but not to the treatment response. In conclusion, our findings suggest that the SNP G2677T/A in the ABCB1 gene, but not β-tubulin mutations, might be a predictor for paclitaxel response and that the interindividual variability in paclitaxel pharmacokinetics might be predicted by ABCB1 and CYP2C8 genotypes and provide useful information for individualized chemotherapy.
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| 2. |
- Rosenberg, Per
(författare)
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On the prognosis and treatment of early stage endometrial carcinoma : Studies with special reference to uterine papillary serous carcinoma
- 1992
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- The prognosis and therapy in the subgroup of endometrial malignancies called Uterine Papillary Serous Carcinoma (UPSC) was investigated. This entity constitutes about 6-8 % of all endometrial carcinomas clinical stage I but, as has been shown here, accounts for one third of the cancer mortality in the early stages of endometrial carcinoma.-The prognostic significance of nuclear atypia, FIGO grade and age was determined in patients with clinical stage 1-11 Uterine Papillary Serous Carcinoma.-DNA-index and S-phase fraction, determined by flow cytometry on formalin-fixed, paraffin-embedded endometrial curettage material was evaluated in relation to nuclear atypia, FIGO grade and age in early stage endometrial carcinoma.-A new method of minimizing the dilution of non-epithelial cells in the malignant curettage material when performing flow cytometry was developed.-The survival and pattern of metastasis in a population-based patient material was investigated -The effects on survival of a new aggressive treatment regimen was assessed.The results show that: Patients with uterine papillary serous carcinoma have a much worse prognosis than do patients with ordinary endometrial carcinoma.DNA ploidy and S-phaseratederived from flow cytometryperformed on disintegrated, previously paraffinembedded, endometrial curettings are important prognostic factors.It is possible to exclude contaminating non-epithelial cells from the DNA analysis by the use of an anticytokeratin antibody, Patients with uterine papillary serous carcinoma clinical stage I have a significantly higher risk of recurrence than patients with non-UPSC. The localisation of the recurrences among the UPSC patients is more similar to that of serous papillary ovarian carcinoma than that of ordinary adenocarcinoma of the endometrium. A primary treatment ofUPSC with a more extensive surgery, adjuvant external radiation and platinum-based chemotherapy seems to improve the outcome.
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