such as the acridines (e.g., Amsacrine); anthracyclines (e.g., Adriamycin); anthraquinones (e.g., Mitoxantrone); and the epipodophyllotoxins (e.g., VP-16). But because only a few of these agents, such as the epipodophylloxins, trap topoisomerases in a nonproductive and stable form, the list of candidate anticancer drugs is narrowed. So, as a first step to further development of antitopoisomerase anticancer drugs, researchers are focusing on how these drugs tie up the enzymes, the character of the enzyme/drug complex, and why it is toxic to actively growing cancer cells.
One theory suggests that topoisomerase poisons trap the enzyme in a useless state, resulting in the loss of an enzyme critical to normal DNA replication. Another posits that the complex of the topoisomerase plus poison itself damages the system. But from the chemotherapist's view, the when and where of topoisomerase inactivation is at least as important as how it is done. Some evidence suggests that a collision of a replication fork with a trapped topoisomerase is the damaging event. There is also the possibility that the ability of an impaired topoisomerase to upset normal replication depends on where its sits on the chromosome. Certain sequences on the chromosome may be more vulnerable to the action of a topoisomerase poison.
Another complication that might affect chemotherapeutic strategies is the finding that inhibiting RNA or protein synthesis protects cells from the cell-killing action of the topoisomerase poison, Amsacrine. So now there is a search for factors that could inhibit, or enhance, the impact of topoisomerase poisons. "The hope [is] that such factors can be manipulated to the chemotherapist's advantage," says Smith.
Still another possibility for enhancing the effect of topoisomerase poisons as anticancer drugs is to coax cells to increase their production of topoisomerases and, hence, their vulnerability to this enzyme's poisons. This is not as farfetched as it sounds. For example, in laboratory studies with human breast cancer cells, it was found that the manipulation of estrogen could stimulate the expression of topoisomerases at a particular point in time and, consequently, the effectiveness of well-timed doses of the topoisomerase poisons, VP-16 and Amsacrine. The end result is the increased killing of cancer cells. This therapeutic strategy will soon begin clinical trials.
Smith says that in the past, "Not knowing the full nature of the cytotoxic interaction between an antitumor agent and its target cell has always undermined our ability to design more effective drugs, to target treatment modalities and to gain some therapeutic advantage by manipulating the biology of neoplastic cells in situ. This situation has now changed for several classes of potent antitumor agents which poison DNA topoisomerases." And there are signs that nuclear proteins other than the topoisomerases will soon be targets for therapeutic agents designed to fight cancer.