Tumor cells, with acquired resistance

Tumor cells with acquired resistance to cisplatin (a major clinical problem) are known to over-express metallothionein, a protein of —61 amino acids, of which 20 are cysteines. Metallothionein is involved with the natural metabolism of Zn(II) and Cu(I), and all the Cys sul-furs are involved in forming terminal or bridging bonds to the 7-10 metals that form clusters on the protein. Petering et al. (29) have recently shown that en is rapidly released from [Pt(en)Cl2] on reaction with metallothionein in vitro and that the rate-determining step does not involve aqua or hydroxo intermediates. 

ZD0473 (formerly AMD473, JM473) was developed in order to overcome acquired or intrinsic (de novo) resistance to cisplatin. Based on the steric bnlk of its methyl-substituted pyridine moiety, thiol snbstitntion and drug inactivation is hindered compared with cisplatin. In several in-vitro studies, ZD0473 was active even in cisplatin-refractory tumor cells, whose key mechanism of resistance was based on thiol substitution. In addition, ZD0473 is also active in cisplatin-resistant tumor cells, in which resistance is based on altered drug transport mechanisms or enhanced DNA repair. 

Although the second generation of platinum drugs is less toxic than cisplatin, many appear to be cross-resistant with cisplatin. Requirements which are influencing the search for new generations of active complexes include (1) lower toxicity to normal cells than cisplatin, (2) activity against tumors with acquired cisplatin resistance, (3) activity against a wider spectrum of types of cancer, and (4) oral activity. 

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. 

The technique is reproducible, more sensitive than methods such as alkaline elution, requires fewer cells and has the important advantage that analysis can be made at the single cell level. It is therefore possible to determine heterogeneity of ISC formation and its repair in a cell population. The method is applicable to studies with cultured cell lines, human lymphocytes and solid tumor tissue. Correlations can therefore be made between both the level of ISCs and the efficiency of their repair with both inherent and acquired resistance to DNA crosslinking agents in vitro and in vivo. 

Tumor cells acquire resistance to methotrexate as the result of several factors, which include the deletion of a high-afQnity, carrier-mediated transport system for reduced folates, an increase in the concentration of dihydrofolate reductase, and the formation of a biochemically altered reductase with reduced affinity for methotrexate. To overcome this resistance, higher doses of methotrexate need to be administered. The effects of methotrexate may be reversed by the administration of leucovorin, the reduced folate. This leucovorin rescue prevents or reduces the toxicity of methotrexate, which is expressed as mouth lesions (stomatitis), injury to the gastrointestinal epithelium (diarrhea), leukopenia, and thrombocytopenia. 

Tumor cells acquire resistance to methotrexate as a result of several factors, which include deletion of a high-affinity, carrier-mediated transport system for reduced folates, an increase in the concentration of dihydrofolate reductase, and the formation of a biochemically altered reductase with... 

Besides being naturally resistant to therapeutics, some CSCs may also acquire further resistance through accumulating mutations following exposure, producing a population of multidrug-resistant tumor cells that can be found in many cancer patients with recurrent diseases [80]. 

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