Drug resistance in cancer

Abstract

Cancer Research UK has recently sponsored a meeting, organized by the UK Medical Research Council, on cancer drug resistance. Several of the molecular mechanisms responsible for this clinical outcome, such as DNA interstrand crosslink repair, apoptosis evasion, cytochrome P450 and P-glycoprotein, were discussed. There was a special focus on leukaemia, breast and ovarian cancer, and the potential use of positron-emission tomography to study anticancer-drug resistance. The progress made in translating these findings to the clinic, like Gefitinib, P-glycoprotein phenotyping, or genome-wide analysis technology, was also discussed. BASIC MECHANISMSIt has been now widely demonstrated that normal primary cells become tumorigenic when expressing hTERT, SV40 proteins LT and ST, and oncogenic ras. We are using the step-wise model of tumorigenesis (Hahn and Weinberg, 2002) to determine whether the ability of human primary embryonic skin fibroblasts to develop drug resistance is exclusive to the transformed state or extends to premalignant cells. Interestingly, cells at early stages of the tumorigenesis process were able to develop doxorubicinresistant derivatives. This demonstrates that, at least in this cell model system, the ability to acquire drug resistance is not a consequence of the accumulation of mutations that occur during the proliferation of a transformed cell, but it is an intrinsic characteristic that appears before the complete set of genetic transforming alterations. We are currently dissecting the minimal set of genetic alterations necessary to switch on the ability to acquire drug resistance, and dissecting the drug resistance signatures by microarray analysis.Drugs that produce DNA interstrand crosslinks between the two complementary strands of the double helix, are among the most widely used and most effective anticancer agents. Victoria Spanswick (London) described a highly sensitive and robust method to determine DNA crosslinks in leukaemia, myeloma and solid tumour samples: the single-cell gel electrophoresis (Comet) assay. Cells isolated from melphalan-treated multiple myeloma patients showed between 42 and 100% repair of radiation-induced DNA crosslinks, whereas no repair was observed in cells from naive patients. These findings suggest that DNA interstrand crosslink repair may be an important mechanism of clinical resistance to melphalan in multiple myeloma (Spanswick et al, 2002). Spanswick and co-workers are currently determining whether molecules involved in the nucleotide excision repair and double-strand break repair pathways are implicated in this process.The cytochrome P450 enzymes are a large family of constitutive and inducible haem-containing oxidative enzymes with roles in the metabolism of xenobiotics and steroid hormone synthesis. Georgia Pass (Dundee) described the use of a mouse model with a conditional deletion in the liver cytochrome P450 reductase (HRN) to study cyclophosphamide (CPA) toxicokinetics and therapeutic response. CPA is an anticancer prodrug that is dependent on cytoc...

Herbal Interactions with Anticancer Drugs: Mechanistic and Clinical Considerations

“…The primary reason for this is because the drug kills both normal and tumor cells and drug levels within tumor cells are too low. Drug resistance and dose-limiting toxicities are the major problems for the success of cancer chemotherapy [6].…”

Combination effects of SC144 and cytotoxic anticancer agents

“…For each level of cytotoxicity, a parameter called the combination index (CI) was calculated according to the following equation 2 , where D 1 and D 2 are the concentrations of the combination required to produce survival f. (D f ) 1 and (D f ) 2 are the concentrations of the individual drugs required to produce f. The value for l was set to one or zero depending on whether the drugs are assumed to be mutually nonexclusive or mutually exclusive, respectively, in their action. By using this method, it is possible to calculate the doses of the individual drugs and the combination required to produce varying levels of cytotoxicity.…”

“…It is well established that the mechanisms of drug resistance to most anticancer drugs are multifactorial [1]. It is well established that the mechanisms of drug resistance to most anticancer drugs are multifactorial [1].…”

Synthesis and Biological Evaluation of Novel Folic Acid Receptor-Targeted, β-Cyclodextrin-Based Drug Complexes for Cancer Treatment

“…The primary reason for this is because the drug kills both normal and tumor cells due to low drug selectivity and drug levels within tumor cells are too low. Drug resistance and dose-limiting toxicities are the major problems for the success of cancer chemotherapy [6]. In the past decade, nano-scaled, targeted drug delivery has attracted much attention as a means to improve the curative effect of existing chemotherapeutic agents while reducing their adverse effects [7], [8].…”