Evaluation of Routes of Administration of Interferon in Cancer: A Review and a Proposal

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Abstract
Interferons are endowed with antiviral and antitumoral activities; the latter particularly has attracted attention, even though it remains uncertain whether it is preferentially due to a direct antiproliferative effect or to enhancement of host-mediated immune responses. Unfortunately, interferons administered in pharmacological doses produce considerable toxicity that is dose-related and that may require cessation of therapy. The administration of interferon has been carried out mostly by intravenous and intramuscular routes. High serum interferon titers have been expected to correlate with therapeutic efficacy. However, there is no such correlation, and certainly interferon levels in the interstitial fluid of target or effector cells would be more critical and informative. Moreover, because they are rapidly filtered by the kidneys, high serum titers are accompanied by considerable renal loss. Thus, several factors, one of which may be the unsuitability of administration routes, may explain the modest therapeutic efficacy of interferon so far observed in cancer. It must be emphasized that interferons and other biological response modifiers are pharmacodynamically unique substances able to elicit unpredictable responses; effects of these drugs depend on the nutritional and metabolic status and immune responsiveness of the host rather than simply on their plasma levels. After reviewing possible routes of administration, a new one, the lymphatic route, appears of interest. The basic strategy is to shift most of the interferon into the lymph pool minimizing direct absorption into the blood. In this way, the lymph/plasma ratio of interferon concentration will resemble that observed during the physiological response and will be greater than 1. Most of the injected interferon will then interact with the lymphoid system, even though eventually it will slowly drain into the blood pool. If the therapeutic index can be shown to be improved in patients, facilitated lymphatic absorption could become a preferential route for the administration of biological response modifiers.