90 The Nature of Biological Diversity 



resistance of Enterococcus stei to sulfonamide (43) , and of Escherichia 

 coli to Aureomycin (44) . In the latter case, electron-transport enzymes 

 in cell-free extracts from resistant cells but not from nonresistant cells 

 were demonstrated to be insensitive to added Aureomycin. Resistance 

 of Erlich ascites cells to mercaptopurine and azaguanine has been 

 associated with the loss of enzymes for conversion of these anticancer 

 agents to their ribotides. (45, 46) . However, even the decreased ability 

 for ribotide synthesis from the anticancer agents may not be the 

 only basis for resistance. Heidelberger et al. (47) have found that 

 although the rate of conversion of fluorouracil to fluorodeoxyuridylate 

 is decreased, the actual amount of fluorodeoxyuridylate present is 

 about the same in the resistant and normal cells, and the resistance 

 was attributed to a decreased ability of the fluorodeoxyuridylate to 

 inhibit the enzymes involved in thymidine synthesis. Increase in the 

 amount of some enzymes may also be associated with resistance. For 

 example, resistance to folic acid analogs in leukemia has been attrib- 

 uted to increased dihydrofolate reductase activity (48) . 



Differences in properties of enzymes from a given microorganism 

 or cellular strain may also be encountered in the well-known phenom- 

 enon of adaptative enzyme formation. In a valuable paper, Halvorson 

 and his colleagues (49) have shown that a highly purified constitutive 

 yeast /?-glucosidase resembles very closely the induced enzyme present 

 in a related species in physical properties and maximal reaction 

 velocity, but that the inducible enzyme has an apparent Michaelis 

 constant one-tenth that of the constitutive enzyme. The data suggest 

 that the two enzymes differ in the fine structure near the catalytic site. 



The present information about enzyme change in adaptation and 

 development of resistance, although meager, is sufficient already to 

 outline some fascinating but difficult problems ahead. As in many 

 areas of research, the more important results and controlling factors 

 may not be visualized at present or may be improperly conceived. 

 Obtaining an understanding of the relations between structure change 

 and the properties of a given enzyme promises to be a challenging 

 but rewarding task. The stepwise appearance of resistance in some 

 cancer cells suggests that there may be considerable randomness in 

 the genetic control of fine structure of enzymes in all cell populations, 

 and thus that resistance might result from the continued selection of 

 the better adapted cells. On the practical side, one may even hope 

 that our degree of biochemical erudition will increase to the point 

 where we can, by planned development of resistance of a cancer cell 

 to one agent, actually render it more susceptible to the action of 

 another agent. 



