The problem of the quiescent cancer cell

1. Antimetabolites and inhibitors of DNA topoisomerase II are relatively ineffective against quiescent cells. 2. Alkylating agents (carmustine, cisplatin) retain significant activity against Q-cells. 3. Of the various cytokinetic reasons why tumors may have slow growth rates (long cycle times, high cell loss factors, differentiation, Q-cells), modeling studies suggest that the presence of a large Q-cell compartment has the most serious implications for chemotherapy. 4. Agents may be active against Q-cells for two reasons: (a) Direct cytotoxicity that is not dependent upon cell proliferation, e.g., direct DNA damage or ATP depletion. (b) Drug accumulation and retention within the cells, resulting in delayed cytotoxicity when the cell re-enters the cell cycle. 5. Q-cells have low rates of RNA synthesis, very low rates of DNA synthesis, and relatively normal ribonucleotide pools. Though earlier results suggest that RNA synthesis is an exploitable target for Q-cell cytotoxic agents, the RNA synthesis inhibitor NSC 366140 did not inhibit RNA synthesis in Q-cells. 6. The pyrazoloacridine, NSC 366140, retained a high level of activity against quiescent cells, as did other pyrazoloacridine compounds with a 9-methoxy substitution. 7. Successful chemotherapy of carcinomas with high Q-fractions will probably require the development of new Q-cell active drugs with sites of action other than DNA. The antimetabolite APP-MP is an example of a non-DNA-directed agent active against Q-cells.