One of the factors of importance in determining the killing of mammalian cells following exposure to a variety of anticancer agents is the proliferative state of the cell population. Generally, proliferating cells are much more sensitive to anticancer agents than are nonproliferating cells. In this review, the cellular aspects of this differential sensitivity are discussed with the hemopoietic stem cell population and tissue culture cells as the focus for the analysis. This phenomenon is not only of concern to the cell biologist but also has implications with regard to scheduling of anticancer agents against human tumors.

https://cancerres.aacrjournals.org/content/canres/35/10/2619.full.pdf

Proliferation-dependent Cytotoxicity of Anticancer Agents: A Review

Summary The drugs [1-β-d-arabinofuranosylcytosine (ara-C), hydroxyurea (HU), 5-hydroxy-2-formylpyridine thiosemicarbazone (5-HP), and camptothecin sodium salt (camptothecin)] considered in this paper markedly inhibit DNA synthesis and are maximally cytotoxic to cells in S phase. In these studies, high-specific-activity thymidine- 3 H (HSA-TdR- 3 H) was used as a control compound which killed cells in S but which did not affect the progression of cells into S. The cell-kill kinetics indicated that ara-C, HU, and 5-HP, unlike camptothecin, blocked the L1210 cells from progressing into S in the presence of the drug. We found that L1210 cells that were blocked in G 1 by HU started moving into S immediately after the drug was removed. Therefore, the time interval between two doses of HU that gave maximal cell kill was the same as that for HSA-TdR- 3 H. However, L1210 cells exposed to ara-C and 5-HP took about 2 hr to recover from the effect of the drug and then progress into S. Therefore, the time interval (between two doses of either ara-C or 5-HP) that gave maximal cell kill was longer than that needed for HSA-TdR- 3 H. Camptothecin did not block L1210 cells from moving into S and, therefore, the cell-kill kinetics with camptothecin were the same as those with HSA-TdR- 3 H. The time for maximal recovery of DNA synthesis by L1210 cells after a single exposure to the drugs was determined. The time for maximal recovery of DNA synthesis correlated well with the interval required for maximal cell kill.

/pdf/cell-kill-kinetics-of-several-s-phase-specific-drugs-t2e3o0pvmv.pdf

Cell-Kill Kinetics of Several S-Phase-specific Drugs

Mathematical methods and computer simulation techniques for describing tumor growth in the presence or absence of chemotherapy are reviewed. The experimental and clinical background is discussed briefly, and several major current issues are identified. These include the development of appropriate descriptions for variable tumor growth rates and kinetic parameters over the entire range of tumor size or maturity, the effects of cell-cycle specific therapy on tumor growth, and the possible implications during treatment of cell-cycle time distributions and degree of correlation between succeeding generations of tumor cells.

Tumor growth and chemotherapy: Mathematical methods, computer simulations, and experimental foundations

The cell cycle and its significance for cancer treatment.

Two functionally distinct classes of growth arrest states in human prokeratinocytes that regulate clonogenic potential.

Summary A number of cytotoxic drugs (mitotic poisons, chemical mutagens, bifunctional alkylating agents, inhibitors of DNA, RNA, or protein synthesis, for a total of 18 agents) have been tested for differences in their lethal effects through the generation cycle of HeLa and Chinese hamster cells in culture. The patterns of age response of cells to each group of agents show some features in common: mitotic poisons, chemical mutagens, and inhibitors of DNA synthesis appear to be most effective on cells in S phase, alkylating agents in M and G 1 , and inhibitors of protein synthesis at the G 1 /S transition, whereas inhibitors of RNA synthesis elicit an X-ray-like age response, i.e. , show grestest activity on cells in M and at the G 1 /S transition. Further differences in lethal action have been defined by microscopic observations of the treated cells; these permit additional distinctions to be made between groups of agents. In the case of asynchronous cell populations, all the agents but 3 give rise to sigmoidal concentration-survival curves (an initial shoulder followed by an exponential decline). The exceptions are nitrogen mustard, which elicits an exponential curve, and hydroxyurea and pederine, which give rise to exponential curves followed by a plateau at about 45% survival level.

F. Mauro

Papers

Age Responses of Cultured Mammalian Cells to Cytotoxic Drugs