Response of a “Resistant” Plasmacytoma to Alkylating Agents and X-Ray in Combination with the “Excision Repair Inhibitors Caffeine and Chloroquine ∗

Abstract

One of the frustrating aspects of tumor therapy has been the resistance developed by tumors to the agents used therapeutically. Alkylating agents and ionizing radiation, which are used frequently in tumor therapy at the present time, are designed to cause damage to the DNA of tumor cells such that they can no longer divide. However, it has been demonstrated that both bacterial (1–4) and mammalian cells (5–8) have the ability to repair such damage to their DNA by means of specific enzymic mechanisms.

Mammalian cell lines have been isolated which show resistance to specific alkylating agents. After the development of this resistance, these cells show a cross resistance to other types of alkylating agents and X-rays with little or no change in their response to such antimetabolites as amethopterin, mercaptopurine, florodeoxyuridine, and azaserine (9). This suggests that a common mechanism may be responsible for the resistance shown by tumors toward alkylating agents and ionizing radiation. Wheeler and Alexander (10) have shown that cytoxan-resistant and sensitive tumors implanted bilaterally in hamsters show the same extent of incorporation of the alkylating agents, cytoxan, nitrogen mustard, and thioTEPA into their DNA fractions when these drugs are administered systemically. This work indicates that the DNA of resistant tumors is just as vulnerable as that of sensitive tumors. Despite the fact that the same amount of damage has been done to the genetic material of both types of cells, one cell line continues to grow almost unimpeded while the other cell line dies. In view of the known presence of repair enzymes in mammalian cells, it was of considerable interest to determine the effect of repair inhibitors on the response of tumors treated with alkylating agents or X-rays.