GENETICS OF SOMATIC CELLS 437 



neoplasms. This is also suggested by their individually different pattern of H-2- 

 variant formation and by differences in the chromosomal picture. 544 At present it 

 cannot be decided whether this individuality is related to the action of methylcholan- 

 threne on some self-reproducing template system or to its possible ability to induce 

 cytogenetic variation in general, with antigenic variation as one consequence and neo- 

 plastic change as another or, finally, to its presumed depressing effect on antibody 

 formation whereby it would permit the establishment of antigenic clones of tumor 

 cells (arising as a secondary consequence of the neoplastic change and representing 

 just another aspect of the well-known variability of tumor-cell populations, eliminated 

 from other tumor types by the host response, but achieving success in this case because 

 of the depression of the immune response). These problems must be attacked by addi- 

 tional investigation. Meanwhile, it is of interest to note that the tumor-specific 

 antigen discovered by Gorer 456 in lymphomas of mice (X factor) is now known to exist 

 in three different forms in three different lymphomas. 457 



Drug resistance and hormonal independence. — Several excellent review articles of recent 

 date are available dealing with drug resistance in neoplasms. 89, 527, 761, 762, 1019 ' 1378 - 

 1406 This phenomenon may be considered from various angles : as a population change, 

 as a cytogenetic phenomenon, as a biochemical mechanism, or as an important factor 

 in frustrating therapy. For the present discussion, only some points will be emphasized 

 which appear relevant for the use of markers for drug resistance in the study of somatic 

 variation. 



From the point of view of population dynamics, available experimental data are 

 strongly suggestive in indicating that the spontaneous appearance of variant cells with 

 a diminished responsiveness towards the drug plays an important role similar to resist- 

 ance to toxic agents in microorganisms or insects. 



This is hardly surprising if it is considered that large differences exist in the primary 

 sensitivity of different neoplasms to the same drug. For every efficient drug so far 

 studied, neoplasms can be found that are highly resistant from the beginning. Even 

 if consideration is limited to a single group of tumors, for example, lymphocytic neo- 

 plasms, and a single group of drugs, such as the folic-acid analogs, there is a wide range 

 of response from natural resistance to striking sensitivity. 761 It is therefore hardly 

 surprising that resistant variants may also appear in populations of sensitive cells. 

 The ease with which resistance develops toward a certain drug in different tumors 

 varies greatly, however. To quote a few examples from our personal experience, it is 

 very easy to make lymphoma LI 2 10 resistant against fluorouracil, while in the Ehrlich 

 ascites tumor, resistance develops with great difficulty and only after prolonged passage 

 in the presence of the drug. 1048 Amethopterin resistance developed easily and regu- 

 larly (in the course of 3-4 passages) in several sublines started with small doses of 

 cells from our ascitic line of L1210, 720 while Law 766 has found that sublines passed 

 independently from the original solid form of this tumor and derived from the same 

 small inoculum in the beginning, vary greatly with regard to the time of appearance 

 of resistant variants. In the experiments of Potter, 1019 prolonged passage in the presence 



