Chemotherapy drug resistance

Carcinogenesis involves a complex series of genetic and biochemical events that enable transformed cells to proliferate, metastasize, migrate to secondary sites, and, sometimes, acquire resistance to chemotherapy. In Sect. 25.4.1, we will discuss how caveolin-1 expression correlates with cancerous growth, a potential mechanism of chemotherapy drug resistance, and how caveolae may be particularly exploited for cancer therapeutic strategies. 

The continuous culture of P. falciparum dramatically altered studies of malaria parasites. In 1997, when Trager and Jensen wrote about the impact of their culture system, they noted it could be usefully applied in nearly every aspect of research chemotherapy, drug resistance,... 

Sparreboom A, Danes R, Ando Y, Chan J, Figg WD. Pharmacogenomics of ABC transporters and its role in cancer chemotherapy. Drug Resist Updat 2003 6 71-84. 

Ilyushina NA, Bovin NV, Webster RG, Govorkova EA (2006) Combination chemotherapy, a potential strategy for reducing the emergence of drug-resistant influenza A variants. Antiviral Res 70 121-131... 

An important factor in the resistance to chemotherapy drugs such as 5-fhiorour-acil and Raltitrexed is an increase in TS expression [72, 37]. The TS enhancer region polymorphism may be one mechanism responsible for increasing TS gene expression. 

Wendel, H. G., Malina, A., Zhao, Z., Zender, L., Kogan, S. C., Cordon-Cardo, C., Pelletier, J., and Lowe, S. W. (2006). Determinants of sensitivity and resistance to rapamycin-chemotherapy drug combinations in vivo. Cancer Res. 66, 7639-7646. 

The answer is c. (Hardman, pp 1161-1162.) An important problem in the chemotherapy of TB is bacterial drug resistance For this reason, concurrent administration of two or more drugs should be employed to delay the development of drug resistance. Isoniazid is often combined with ethambutol for this purpose. Streptomycin or rifampin may also be added to the regimen to delay even further the development of drug resistance. 

Early administration of effective combination chemotherapy at a time of low tumor burden should increase the likelihood of cure and minimize emergence of drug-resistant tumor cell clones. Combination regimens have historically been more effective than single agent chemotherapy (Table 61-1). 

Finally, therapeutic sequencing of different hormonal agents is fast becoming a common clinical practice, and fulvestrant is a good treatment choice to extend the opportunity for using endocrine therapies before reliance upon cytotoxic chemotherapy is necessary. Further research is required in order to evaluate the optimal sequence, both in clinical practice as well as in the laboratory, to choose the correct treatment of breast cancer in each person after the appearance of tamoxifen-induced drug resistance (Robertson 2004 Osipo et al. 2004 Johnston 2004 Robertson et al. 2005). 

Epothilones A, B and E (4,5 and 6) (Fig. 2) are representative members of a new class of bacterially derived natural products which exhibit potent biological activity. Isolated by Hofle and coworkers [6] from a soil sample collected near the Zambesi river, the compounds have provided a great deal of excitement in the scientific community due to their potent cytotoxicity against a number of multiple drug-resistant tumor cell lines and because of the mechanism by which they exert this effect. Like Taxol [7], the epothilones promote the combination of a- and 3-tubulin subunits and stabilize the resulting microtubule structures. This mode of action inhibits the cell division process and is, therefore, an attractive strategy for cancer chemotherapy [7,8]. 

To date, 16 GST isozymes have been found in humans [48]. Studies of several cancer tissues have revealed the overexpression of different GST isozymes, with GST Pl-1 (GST Pi, GST ji) being the most predominant. For this reason, GST Pl-1 is regarded as a potential tumor marker [5,49-53]. The high expression levels of GST Pl-1 (up to 2.7% of the total cytosolic protein [52]), combined with its detoxification role against xenobiotics, make GST Pl-1 a major player responsible for drug resistance in patients undergoing anticancer chemotherapy [49]. 

Cyclopamine also interferes with cholesterol metabolism that results in decreased cholesterol synthesis and the accumulation of late biosynthetic intermediates. Cyclopamine was evaluated as an inhibitor of multi-drug resistance in tumor cells. Intrinsic or acquired resistance of tumor cells to cytotoxic drugs is a major cause of failure of chemotherapy. Both cyclopamine and the spirosolane alkaloid tomatidine from tomatoes act as potent and elfective chemosensitizers in multidrug-resistant cells (Lavie et ah, 2001). Therefore, plant steroidal alkaloids, such as cyclopamine and tomatidine, or their analogs, may serve as chemosensitizers in combination with chemotherapy and conventional cytotoxic drugs for treating multidrug-resistant cancers. 

Fidock DA, Eastman RT, Ward SA, Meshnick SR. (2008) Recent highlights in antimalarial drug resistance and chemotherapy research. Trends Parasitol 24 537-544. 

After over half a century of chemotherapy research, cancer remains one of the most difficult life-threatening diseases to treat, a consequence of factors that include limitations of animal models, tiunour diversity, drug resistance and the side effects of therapy. Although there have been successes, most notably in treatment of testicular cancer [1], chemotherapy can currently still offer only a modest increase in survival time in the majority of advanced disease cases [2], The incidence of cancer is increasing due to ageing populations in most countries, and it has been estimated that in 20 years time there will be 20 million new cancer patients worldwide each year [3]. An optimistic view, however, is that in the coming decades advances in prevention, detection and treatment will see cancer becoming considered not as a fatal but as a chronic disease [3]. 

The lymph node microenvironment represents a niche where CLL cells interact with different types of cells including monocyte-derived nurse-like cells (NLC), CD3+ CD4+ CD154+ T cells, mesenchymal stromal cells, dendritic cells, and endothelial cells (15). In addition to cell-cell interactions, CLL cells are also exposed to a variety of soluble factors such as antigens, cytokines, and chemokines (2). It is the combination of such signals that renders CLL cells less susceptible to chemotherapy and promotes clonal evolution and drug resistance. Thus, the role of the microenvironment needs to be carefully considered in order to develop novel and more effective therapies for CLL treatment (16). In particular, the efficacy of new drugs must be evaluated under experimental conditions that recapitulate (or at least partially mimic) the CLL microenvironment. 

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-... 

---