Can Chemotherapy Be Extended to Include the Intracellular Disease Agents?

The present limits of successful chemotherapy do not quite coincide with the line of division between extracellular and intracellular disease agents. Thus chemotherapeutic benefit in experimental murine typhus has recently been reported by Moragues, Pinkerton, and Greiff (1944), and in human epidemic typhus by Yeomans and others (1944). Chemotherapeutic benefit is well authenticated for infections with viruses of lymphogranuloma venereum, mouse pneumonitis, trachoma, inclusion conjunctivitis, and most recently is reported for experimental ornithosis and psittacosis (Heilman and Herrell, 1944). Yet the pathogenic rickettsiae and the viruses of the lymphogranuloma-psittacosis group are obligate intracellular parasites. Nor is the limit of current chemotherapeutic effectiveness coincident with the limit of simple cellular organization of the disease agent (Mudd and Anderson, 1944); vaccinia virus and even coilphage have been shown by electron microscopy to possess cell-wall, inner protoplasm, and even finer structural differentiation; yet no authenticated success in chemotherapy with viruses other than those cited above is known. It is interesting and possibly significant that those intracellular agents which now respond to chemotherapy are the rickettsiae, which are intermediate in size between pathogenic bacteria and the viruses, and members of the lymphogranuloma-psittacosis group, which are the very largest of known viruses. Several approaches to a chemotherapy of intracellular disease agents can be formulated: (1) Direct chemical action on the disease agent. The long list of empirical trials has recently been reviewed by Kramer, Geer, and Szobel (1944). See also Parker and Diefendorf (1944) and Klein, Kalter, and Mudd (1945). (2) Interference with the key-to-lock relationship of virus to susceptible host cell. This is precisely what specific antiphage (antiviral) antibody does when used prophylactically, as the experiments of Kalmanson and Bronfenbrenner (1943) on reversible serum inactivation of bacterial virus show. It is hard to imagine, however, what more (if as much) could be expected in this connection from any chemical agent than is now achievable by specific antiserum-namely, prophylaxis which is efficient, but therapeutic action which is very limited indeed. (3) Rational investigation of cell metabolic systems and their selective inhibition. This approach seems to the writer incomparably the most promising one. The essential attribute of a chemotherapeutic agent is a selective action on a component essential to the continued existence of the parasite within its host. Sir Henry Dale in a recent review of the history of chemotherapy (1943) clearly