Cancer chemotherapy combination drugs

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]. 

Perhaps psychopharmacological treatments for psychotic disorders in the future will need to borrow a chapter out of the book of cancer chemotherapy and HIV/ AIDS therapy, in which the standard of treatment is to use multiple drugs simultaneously to attain therapeutic synergy. Combination chemotherapy for malignancy uses the approach of adding together several independent therapeutic mechanisms. When successful, this results in a total therapeutic response that is greater than the sum of its parts. 

Some common anticancer drug combinations and the types of cancer in which they are used are listed in Table 36-8. These drug combinations are often indicated by an acronym of the drug names. For instance, FAC indicates a regimen of fluorouracil, doxorubicin (Adriamycin), and cyclophosphamide. These abbreviations are used to summarize drug therapy in a patient s medical chart, so therapists should be aware of the more common chemotherapy combinations. 

Cancer chemotherapy is only one method of treating neoplastic disease. The other primary weapons in the anticancer arsenal are surgery and radiation treatment.18,61 The choice of one or more of these techniques depends primarily on the patient, the type of cancer, and the tumor location. In many situations, chemotherapy may be the primary or sole form of treatment in neoplastic disease, especially for certain advanced or inoperable tumors, or in widely disseminated forms of cancer, such as leukemia or lymphoma.6 In other situations, chemotherapy is used in combination with other techniques, such as an adjuvant to surgery and radiation treatment.18,27 Primary examples of adjuvant cancer chemotherapy include using anticancer drugs following a mastectomy or surgical removal of other carcinomas.19,54,43,61... 

Tetrahydrofolate cofactors participate in one-carbon transfer reactions. As described above in the section on vitamin B12, one of these essential reactions produces the dTMP needed for DNA synthesis. In this reaction, the enzyme thymidylate synthase catalyzes the transfer of the one-carbon unit of N 5,N 10-methylenetetrahydrofolate to deoxyuridine monophosphate (dUMP) to form dTMP (Figure 33-2, reaction 2). Unlike all of the other enzymatic reactions that utilize folate cofactors, in this reaction the cofactor is oxidized to dihydrofolate, and for each mole of dTMP produced, one mole of tetrahydrofolate is consumed. In rapidly proliferating tissues, considerable amounts of tetrahydrofolate can be consumed in this reaction, and continued DNA synthesis requires continued regeneration of tetrahydrofolate by reduction of dihydrofolate, catalyzed by the enzyme dihydrofolate reductase. The tetrahydrofolate thus produced can then reform the cofactor N 5,N 10-methylenetetrahydrofolate by the action of serine transhydroxy- methylase and thus allow for the continued synthesis of dTMP. The combined catalytic activities of dTMP synthase, dihydrofolate reductase, and serine transhydroxymethylase are often referred to as the dTMP synthesis cycle. Enzymes in the dTMP cycle are the targets of two anticancer drugs methotrexate inhibits dihydrofolate reductase, and a metabolite of 5-fluorouracil inhibits thymidylate synthase (see Chapter 55 Cancer Chemotherapy). 

It is very well known that the phenothiazines alone possess no antitumour and/or antineoplasma activity. But when they are applied in combination with other drugs, the phenothiazines can increase the anticancer activity and provoke a decrease of mutagenesis, diminishing the cytotoxic effects caused by radiation, carcinogenic chemicals and multidrug resistance (MDR). The positive effects of a simultaneous chemotherapy of cancers by combining... 

In summary, although novel therapies not based upon nucleoside derivatives are being put forward into clinics, combined treatments still rely upon nucleoside derivatives, thus making the type of studies summarized above still mandatory for a better understanding of interindividual differences in patient response to therapy. Actually, as previously discussed, nucleoside transporter expression is variable in human tumors, and evidence provided so far indicates a putative role of NTs in nucleoside-derived drug bioavailability and responsiveness. Prospective clinical studies focused on NTs as biomarkers of drug metabolism and action are required to better establish the role these membrane proteins might play in cancer chemotherapy. This would eventually lead to the analysis of NT expression patterns as suitable predictors of response to therapy and patient outcome. 

His studies also revealed that after a period of treatment, some trypanosomes or spirochaetes became resistant to the administered drugs, presumably because their chemoreceptors became less specific for the drug. The adverse effects elicited in the patient thus increased as the antimicrobial effect decreased. One solution to this problem was to administer mixtures of drugs with affinities for different classes of chemoreceptors. In this way, smaller quantities of the drugs could be used, and there was an increased chance that the microorganism would be completely eliminated before it had time to become resistant. Combination chemotherapy, the mainstay of modem cancer chemotherapy, arose from experiments of this kind. 

Cancer occurs when mutated cells divide uncontrollably, taking up space and spreading to distant parts of the body. Treatment is usually with a combination of surgery, irradiation and chemotherapy. The aim of chemotherapy is to interfere with cell division in tumour cells without damaging normal healthy cells. However, because cancer cells are similar to normal cells, chemotherapy is toxic to rapidly dividing cells in bone marrow, hair follicles and the gastrointestinal tract. Resistance to cancer chemotherapy can occur and for this reason combinations of drugs with different mechanisms of action provide the best chance of a successful cure. 

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