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The purpose of the present investigation was to determine if RES activity was altered after the infusion (bolus i.v. injection over approximately 3-5 min) of hydroxyethylstarch (HES). RES function was determined by vascular clearance of 51Chromium-labeled sheep erythrocytes and the subsequent uptake into the liver, spleen, lungs, and thymus at 1 hr, 3 hr, 6 hr, 1 day, 3 days, and 7 days post infusion. Infusion with the low doses of HES (20 and 40 ml/kg) produced changes in vascular clearance which were comparable to physiological saline. Infusion with 80 ml/kg HES produced a biphasic response with a modest suppression of vascular clearance (i.e., 151% increase in half life) and hepatic phagocytosis (50%) during the first 6 hours after injection, followed by recovery at 24 hours and a stimulation in hepatic uptake (42%) after 3 days. These effects by HES were compared to those produced by infusion with 80 ml/kg HSA, a comparable colloid and with 80 ml/kg pyran copolymer, a positive control.

We have used a murine renal adenocarcinoma of spontaneous origin (Renca) inplanted in the peritoneal cavity to study the therapeutic potential of biological response modifiers (BRMs) used alone or in conjunction with chemotherapy. This tumor model is therapeutically challenging since following intraperitoneal (i.p.) injection, the tumor grows progressively with hemorrhagic ascites, abdominal metastases to lymph nodes, liver, spleen, most serous membranes, and, in some animals, metastases to extra-abdominal sites (lungs). In the absence of therapy, death invariably occurs within 36 +/- 2 days. The tumor is efficiently lysed in 4 hours by peritoneal cells isolated from mice treated with BRMs. Both MVE-2 and rIL-2 significantly increased the survival time of tumor-bearing mice, but only treatment with MVE-2 led to definite cures of i.p. Renca. A single i.p. injection of MVE-2 cured 20% of the tumor-bearing mice, while repeated i.p. administration of this drug at 12 day intervals cured 70% of i.p. Renca-bearing mice. Combined therapy with doxorubicin hydrochloride and a single dose of MVE-2 cured 90% of tumor-bearing animals. The superior therapeutic efficiency of MVE-2 compared to that of the rIL-2 may be due to its ability, after i.p. inoculation, to generate and maintain high levels of cytotoxic effector cell activity for an elevated period of time within the peritoneal cell population. Additionally, MVE-2 augments effector cell activity in the liver, lungs, spleen, and blood and may therefore more efficiently interfere with metastasis formation in those compartments. The additive effects of MVE-2 and the chemotherapeutic agent suggest that more effective therapy may be achieved by the combination of immunotherapy with BRMs with chemotherapeutic drugs.

Many naturally occurring polyanionic materials are known, each of which possesses its own set of physiological properties. Recently, a variety of synthetic polyanions have become available, and their physiological properties have been compared with the naturally occurring polyanions. Probably the most widely investigated synthetic polyanion is the 1:2 regularly alternating cyclo-copolymer (DIVEMA) (Eq. 1) of divinyl ether (DVE) and maleic anhydride (MA), first discovered in these laboratories in 1951 [1], This material has been investigated extensively, both from the standpoint of its chemical structure [2] and its antitumor activity [3]. Although certain aspects of its structure remain to be determined [4], it has been shown to possess a wide spectrum of biological activity [5] and is an interferon inducer [3]. Many structural modifications of DIVEMA have been synthesized which also possess antitumor activity and interferon-inducing capability [6].

Administration of BCG and Corynebacterium parvum is known to cause depression of the hepatic microsomal enzyme system (HMES) in mice. In the present study we explored the effects on HMES of two chemical immuno-adjuvants, one of which (pyran copolymer) with peculiarly long-lasting biological activities. The two synthetic immunoadjuvants proved to be potent HMES inhibitors and, for pyran copolymer, peak levels of inhibition concurred with maximal macrophage activation. The inhibition was largely dose-dependent and could not be prevented by immunopharmacologic maneuvers that are known to block the C. parvum effect on HMES. The possibility is discussed that common mechanism(s) underlie the depression of HMES by immunoactive substances of both bacterial and chemical origin.

A series of Maleic anhydride divinyl ether (MVE) polyanions, synthesized with molecular weight ranging from 12500 to 52600, were found capable of enhancing macrophage tumoricidal activity of MBL-2 leukemia cells. These agents also augmented Natural Killer cell activity against the YAC lymphoma and M109 adenocarcinoma cell lines.

The effect of pyran copolymer, injected into mice bearing the M109 Madison lung carcinoma, on serum concentrations of lysozyme, β-glucuronidase, and N-acetyl-β, D-glucosaminidase was studied and compared with that of other immunoadjuvants. Increases in lysozyme levels ranging from 50 to 100% were observed after injection of pyran, BCG and Bru-Pel; increases in the levels of the other enzymes were less consistent. Other immunoadjuvants were less effective in raising serum concentrations of lysosomal enzymes. The findings were correlated with the results of previous studies on macrophage activation and antineoplastic action produced by these immunoadjuvants and suggest that serum levels of lysozyme can serve as indices of these effects.