Inhibition of murine RNA tumor virus replication and oncogenesis by chloroquine

Abstract

7 -Chloro -4-( 4-diethylamino-1 -methylbutylamin0)quinoline diphosphate, chloroquine, is an antimalarial drug that has also been studied for its effects on repair processes in cells after irradiation (Gaudin and Yielding, 1969; PazmiRo and Yuhas, 1974). In addition, it has been shown to inhibit the replication of several non-oncogenic animal viruses in cell culture (Mallucci, 1966;Shimizu et al., 1972), but the molecular mechanism of inhibition is not known. Shimizu et al. (1972) showed that chloroquine selectively inhibits the synthesis of vesicular stomatitis virus RNA without affecting cellular R N A synthesis, and Mallucci (1966) reported a n inhibitory effect of chloroquine on the growth of mouse hepatitis virus, which he attributed to its stabilizing effect o n lysosomes. However, Wilson (1972) demonstrated that chloroquine did not prevent virusinduced release of acid phosphatase from lysosomes and further showed that the growth of Newcastle disease virus in chick embryo fibroblasts was normal when chloroquine was present at a concentration of 50 pglml. Lancz et al. (1971) reported that the drug inhibits replication of herpes simplex virus in HeLa cell cultures; and Banfield and Kisch (1973) were able to confirm these observations in cell culture but could not demonstrate a similar inhibition in vivo.This report presents some preliminary results on the effects of chloroquine o n the replication and oncogenesis of mouse R N A tumor viruses. The results show that chloroquine can inhibit the induction of sarcoma by Moloney sarcoma virus and of splenomegaly by Rauscher leukemia virus. Cell culture experiments indicate that the drug inhibits some step in viral replication.

Membrane fusion mutants of Semliki Forest virus.

“…If the fusion activity at low pH were an experimental artefact, as has been recently suggested by Brown and co-workers (6,25), the pH in vacuoles of the endocytic pathway and the pH dependence of fusion would be irrelevant for entry and infection . Viruses of many families (orthomyxo-, rhabdo-, toga-, retro-, and herpes viruses) have been reported to be inhibited by weak bases (14,18,30,35,37,39,45), and by carboxylic ionophores (27,38), which elevate lysosomal and endosomal pH (31,32). Of these, the first three virus families have now been shown to possess low pH-dependent membrane fusion activity .…”

The entry of enveloped viruses into cells by endocytosis

“…The observations that several weak bases inhibit infection by retro-and Herpes viruses has suggested that these viruses may also infect their host cells through an intracellular route (Wallbank et al, 1966;Banfield & Kisch, 1973;Pazmino et al, 1974;Anderson & Nex0, 1983). In addition, paramyxovirus infection can also be inhibited by weak bases (Skehel et al, 1977;.…”

Attenuation of murine coronavirus infection by ammonium chloride

“…While a seemingly the rhabdovirus, vesicular stomatitis virus limited number of viruses such as Sendai (Schlegel et aL, 1982), and the togavirus, virus effect entry into the cell by a direct Semliki Forest virus fusion process of viral envelope with host Marsh et al, 1983), the endocytic process plasma membrane (Choppin and Compans, has been shown to involve uptake into 1975), it now appears that most lipid-clathrin-coated pits similar to those imenveloped viruses are taken up by an plicated in the receptor-dependent uptake of hormones and other proteins (Dickson Sciences Centre,3330 Hospital Drive NW, Calgary, endosome into the cytosol addressed. Maeda et al, 1981;White et aL, 1981 Lysosomotropic agents such as ammonium chloride and a variety of amines have been demonstrated to inhibit the replication of viruses from the toga- (Helenius et d, 1982), rhabdo- (Schlegel et cd., 1982), orthomyxo- (Kato and Eggers, 1969), retro- (Pazmino et aL, 1974), and herpes- (Shimizu et al, 1972) virus families. A common characteristic of these agents is that they are weak bases and accumulate within acidic intracellular compartments, notably lysosomes, thereby elevating pH (Ohkuma and Poole, 1978).…”