Towards tumor therapy with interferons, part II. Interferons: in vivo effects.

PHARMACOLOGY AND TOXICOLOGY T HE PHARMACOLOGY of interferons has been studied with human leukocyte interferon and with mouse and rabbit interferons. These have a short half-life in the blood, irrespective of the route of administration, though the most rapid clearance follows the intravenous route; intramuscular injections result in peak blood levels after 2-4 hr, lasting for 4-6 hr. With intramuscular doses of 2 x lO IU*/kg body weight in man, one can maintain about 100 U of interferon activity/ml of plasma for 12 hr.’3 The plateau phase can be prolonged with a higher initial dose.4 This slow clearance phase is believed to be due in part to the release of previously tissue-bound interferon. Binding and subsequent elution have been documented for cultured cells.5 Only a fraction of the interferon administered intramuscularly can reach the respiratory tract, the cerebrospinal fluid, the eye fluids, and the brain, although these compartments may contain high titer endogenous interferon when they F arbor viral infections. There is minimal urinary or intestinal excretion. When lactating mice are treated with interferon inducers, some interferon can be found in the milk and it appears to protect suckling animals. This is a unique instance of administration effective per os. The pharmacology of humanfibroblast interferon is less well known, and it has recently become obvious that it is quite different from that of leukocyte interferon. In vitro, fibroblast interferon has all the properties of an interferon, but it has, so far, been less effective therapeutically.67 Clearance is more rapid, and it may not be detectable at all in the circulation following i.m. administration.8 It appears very sensitive to inactivating factor(s) present in body fluids and/or extracts of muscle tissue.9”#{176} It may actually have desirable properties, having been particularly effective in slowing down the rate of multiplication of osteogenic sarcoma cells in vitro.” Mouse interferon is also rapidly cleared from blood and inactivated by muscle extracts.’2 Moreover, when mouse “leukocyte” interferon (produced by mouse spleen cells) was compared to the mouse 7ibroblast” (L-cell) interferon, their major molecular species were found identical physicochemically, biologically, and autigenically. Thus, the mouse seems to lack an equivalent of human leukocyte interferon.’3 Mouse interferon also seems less effective as an antitumor agent than human leukocyte interferon (it does not induce tumor regressions), perhaps because, like human fibroblast interferon, it is rapidly inactivated in vivo. Human leukocyte interferon preparations with a specific activity of 106 lU/mg protein (O.l%-l% interferon protein) are well tolerated when given subcutaneously, intramuscularly, or even when injected intravenously or intracisternally. Side effects have consisted of dose-related febrile responses, usually more marked following the first few injections, whatever the route of administration. Transient myalgia and chills following each injection have been reported with daily doses greater than I .7 x I O lU/kg body weight. Fatigue and malaise are also cause for complaints, particularly by older or debilitated patients.”3’4”5 The use of more purified preparations ( I O lU/mg