Resistance to drugs and other agents

Ehrlich (1909) thought that resistance was caused by stepwise withdrawal, or masking, of the receptor by the organism. However, this is not the case, and it remained for Yorke et aL (1931) to show that, at least in trypanosomes, resistance is caused by diminution of uptake by the parasite. 

Ehrlich encountered several distinct types of resistance in trypanosomes. 

Parasites which had become resistant to trypan red resisted all other azodyes. Some other strains, which were resistant to Atoxyl (p-amino-phenylarsonic acid) (6./), resisted all other phenylarsonic acids, and a third type, resistant to parafuchsin 6,54) resisted all other triphenylmethanes. Yet a strain resistant to one of these three classes of drugs did not resist the other two classes unless specially trained to do so. 

As far as is known, resistance in trypanosomes always takes the same form the parasite so modifies the chemistry of its surface that the drug is no longer taken up but remains behind in the medium (Yorke et aL 1931). On the other hand, a susceptible trypanosome can accumulate in its interior a 500 times greater concentration of arsenic than exists in the external medium (Eagle, 1945). 

To-day a rough distinction is made between natural and acquired resistance, as illustrated by the following three cases. The Mycobacterium that causes human tuberculosis has natural resistance to penicillin Staphylococcus aureus (the common yellow pus organism) has many strains that are susceptible to penicillin but can easily acquire resistance to it Streptococci lack natural resistance to penicillin and do not acquire it either. 

Resistance is a widespread, but not universal, phenomenon. Its possibilities, although frightening in special cases (insects to most known insecticides the staphylococcus to most of the formerly useful antibiotics), are not unlimited. Replica-plating discloses that E. coli can be made to achieve only a threefold increase in resistance to chloramphenicol (Cavalli-Sforza and Lederberg, 1956), and this seems to be representative of what natural selection usually accomplishes. 

The four main types of resistance (arising by natural selection or by gene-transfer) will now be described. 

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The mechanism of L-1210 resistance to cisplatin and other platinum antitumour agents remains to be clearly defined. Both Waud [77] and others [78] suggest that reduced cisplatin uptake may be responsible in part for the resistance of the cell line. It has also been found that glutathione levels are high in human ovarian carcinoma cells made resistant to cisplatin in vitro [79]. However, reduction in the level did not alter the resistance to the drug [80]. Decreases in amino-acid transport and changes in amino-acid substrate specificities have also been suggested as the basis for the resistance [81], but definitive evidence has been difficult to obtain. 

Clarithromycin has been shown to be an effective prophylactic agent against MAC infection in patients with advanced HIV infection. In a prospective, doubleblind, placebo-controlled trial, clarithromycin prevented 69% of the expected cases of MAC disease [64]. Other studies have demonstrated that clarithromycin alone or in combination with rifabutin prevents MAC infections in AIDS patients and prolongs survival [65, 66]. However, a large prospective study failed to show that the combination of clarithromycin plus rifabutin combination was more effective than clarithromycin alone [67]. Drug-resistant MAC has been reported in 29-58% of patients who developed disseminated infection while taking prophylaxis with clarithromycin [64, 67]. Resistance to clarithromycin and other macrolides is a serious potential problem due to cross-resistance with azithromycin that narrows the therapeutic options available for MAC disease [68]. 

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. 

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