Acquired drug resistance

Drug resistance in vitro and probably in vivo results both from inhibition of influx of the vinca alkaloids and, perhaps more frequently, from promotion of their efflux out of cells (34,35). Until relatively recently, the former mechanism was thought to predominate, and, indeed, certain acquired drug-resistant states are clearly associated with the loss of membrane proteins which can be shown to bind and transport agents into cells (34). However, other resistant states have been shown to be associated with the acquisition of membrane transport proteins which remove toxins (and, therefore, chemotherapeutic agents) both from normal and malignant cells. 

Several reasons have been cited for the limitations of the use of chemotherapy in the treatment of malignant glioma. Inherent and acquired drug resistance and the lack of good drug penetration through the blood-brain barrier have both been cited as obstacles. Sev-... 

Boehm T, Folkman J, Browder T, et al. Antiangiogenic therapy of experimental cancer does not induce Acquired drug resistance. Nature (Lond) 1997 390 404-407. 

The in vitro system has some limitations and it can be used only as a model to address acquired drug resistance, because cell lines may not accurately reflect the in vivo situation of patients treated with anticancer drugs. In vivo analysis using patient samples to study anti-cancer drug resistance are described in the published literature. Chang and coworkers (64) showed that the gene-expression patterns from mRNA derived from needle biopsies of breast cancer patients treated with the anticancer drug, docetaxel, could be predictive of response to the therapy. 

We applied the similar strategy for ultrasensitive quantification of a clinically important anticancer drug, paclitaxel. Although conventional high-dose therapeutic regiments of paclitaxel has been widely used for solid tumors treatment, severe side effects and acquired drug resistance are becoming major issue in clinical. Numerous... 

Figure 13.1 Acquired drug resistance in cancer involves a complex mechanism mediated by many proteins. Some of these are illustrated in this schematic cell. Figure provided by Y. Hathout.

Drug malabsorption may contribute to the emergence of acquired drug resistance. It has been described in HIV-infected patients with advanced disease (37), and also in immunocompetent patients (38). Thus, in addition to the use of directly observed therapy to ensure compliance, it is advisable to monitor antimycobacterial drug concentrations routinely in such patients. Practical proposals for the choice of antituberculosis drugs in special circumstances, including drug resistance, have been made (39). 

A second way in which bacterial cells can acquire drug resistance is by gaining that resistance from another bacterial cell. This occurs because it is possible for genetic information to be passed on directly from one bacterial cell to another. There are two main methods by which this can take place—transduction and conjugation. 

The ease with which different bacteria acquire resistance varies. For example, Staphylococcus aureus is notorious for its ability to acquire drug resistance due to the ease with which it can undergo transduction. On the other hand, the microorganism responsible for syphilis seems incapable of acquiring resistance and is still susceptible to the original drugs used against it. 

Catherine C. Fenselau is a professor of chemistry and biochemistry at the University of Maryland, College Park. She has been a pioneer in the application of mass spectrometry in biomedical research. Her current interests include the use of proteomic strategies to investigate cellular mechanisms of acquired drug resistance and as the basis for detection and analysis of... 

Figure 15.2 Typical method for developing acquired drug-resistant cells lines.

What is the difference between inherent (natural) and acquired drug resistance ... 

Drug resistance is a major problem that limits the effectiveness of chemotherapies used to treat cancer. Acquired drug resistance refers to the problem that tumors not only become resistant to the drugs... 

Nyce, J.W., Drug-induced DNA hypermethylation a potential mediator of acquired drug resistance during cancer chemotherapy, Afatot. Res., 386 (2), 153-161,1997. 

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