Biomedical subjects

Sally A Coulthard

Publications and source records attributed to Sally A Coulthard.

3 recordsLinked to original sources

PubMed2003

Chemotherapy individualization.

The current practice of dosing patients with anticancer drugs based on body size, leads to a large degree of interpatient variation in clinical outcome following standard doses of chemotherapy. Some patients may fail to respond to treatment, whilst others experience unacceptable side effects. Recent studies have identified more rational approaches to drug dosing, based on patient characteristics such as renal function, pharmacogenetic factors, and drug metabolizing activity. These can be used together with therapeutic drug monitoring and adaptive dosing to achieve a targeted systemic drug exposure in each patient, which may lead to more consistent clinical outcomes in patients receiving comparable chemotherapy dosing regimens. The purpose of this review is to present some approaches to chemotherapy individualization, examples of how this might be applied, and speculation as to how recent advances in pharmacogenetics may lead to further dose-optimization. Whilst it is hoped that the design of new agents, targeted to specific genes involved in oncogenesis, will lead to increased success in the treatment of cancer patients, it is essential that the drugs currently available are used to their maximum potential.

Animals↗

PubMed2003

Molecular diagnostics: a healthcare perspective.

Recent progress in the development of molecular diagnostics in medicine has been rapid and the hope has been expressed by some people that it will soon be possible to have a detailed 'genetic readout' to assist in the diagnosis of treatment of a variety of diseases. However, such an outcome may be neither achievable nor desirable when viewed from the perspective of suppliers of healthcare.

Cost-Benefit Analysis↗

PubMed2002

The effect of thiopurine methyltransferase expression on sensitivity to thiopurine drugs.

Although the thiopurine drugs 6-mercaptopurine (6-MP) and 6-thioguanine (6-TG) are well established agents for the treatment of leukemia, controversies remain regarding their main mode of action. Previous evidence has suggested that although 6-TG exerts a cytotoxic effect through incorporation of 6-thioguanine nucleotides into newly synthesized DNA (DNA-TGN), an important component of the mode of action of 6-MP is inhibition of purine de novo synthesis (PDNS) through the production of S-methyl-thioinosine 5'-monophosphate (MeTIMP), not formed in cells exposed to 6-TG. We have shown that thiopurine methyltransferase (TPMT) modulates this effect. By transfection of the human TPMT gene using an inducible system to produce a 3.8-fold increase in TPMT activity in the ecdysone receptor 293 embryonic kidney cell line, we demonstrated a 4.4-fold increase in sensitivity to 6-MP. This was associated with a rise in intracellular levels of MeTIMP but a decrease in levels of DNA-TGN. In contrast, induction of TPMT produced a 1.6-fold decrease in sensitivity to 6-TG, a decrease in levels of DNA-TGN, and an increase in levels of methylated thioguanosine monophosphate. Exposure of cells to equitoxic doses of drug showed similar incorporation of DNA-TGN for 6-TG but for 6-MP significantly reduced DNA-TGN in TPMT-induced compared with uninduced cells. For equitoxic doses of 6-MP, equivalent levels of MeTIMP correlated with equivalent amounts of PDNS. These observations suggest that intracellular TGN levels do not give an accurate reflection of cytotoxic potential in patients treated with 6-MP, because different levels of DNA-TGN may be associated with equitoxic effects.

Cell Line↗