The inhibition of colon-26 adenocarcinoma development and angiogenesis by topical diclofenac in 2.5% hyaluronan.

Topical diclofenac in 2.5% hyaluronan inhibits basal cell carcinoma, actinic keratosis, and murine colon-26 growth in vivo. colon-26 tumor growth was preceded by angiogenesis and reduced apoptotic and mitotic indices. Diclofenac reduced proliferation and viability in vitro, and stimulated apoptosis. Hyaluronan inhibited proliferation and viability at 1 mg/ml but was inactive below this level. Topical application of diclofenac inhibited tumor prostaglandin synthesis and retarded angiogenesis and tumor growth (ratio of treatment:control, 0.174). The mitotic index remained unaltered in vivo, whereas the apoptotic index and necrosis were increased. Topical vehicle exhibited slight antitumor and antiangiogenesis activity. The substantial quantities of diclofenac delivered locally in hyaluronan may exhibit antitumor activity in similar fashion to those seen in vitro and explain its clinical efficacy.

Carboxyimamidate, a low-molecular-weight polyelectrolyte with antitumor properties and low toxicity.

A new polyelectrolyte was synthesized and evaluated for antitumor activity. The product is a derivative of ethylene/maleic anhydride copolymer of low molecular weight (Mn approximately equal to 1100). The anhydride groups were first converted to the half-amide, half-ammonium salt by reaction with ammonia. A percentage (14-25 wt %) of these groups was further converted to the imide by heating. The product, carboxyimamidate (Carbethimer, N-137) inhibited the growth of a number of solid tumors in vivo. Sensitive tumor models included Lewis lung carcinoma, Madison 109 lung carcinoma, M5076 ovarian tumor, colon carcinoma 26, B16 melanoma, and P815 mastocytoma. Activity was dose related between nontoxic dose levels of 300 and 2000 mg/kg ip.

Effects of hyaluronic acid on fibroblast behavior in peritoneal injury.

The process of intraperitoneal adhesion formation is affected by macrophages and fibroblasts which are major components of postsurgical peritoneal repair. Hyaluronic acid (HA) has been shown to affect cellular behavior. We studied the effects of HA on experimental adhesions in vivo and its in vitro effect on cultured postsurgical macrophages and fibroblasts. Experimental adhesions were facilitated by laparotomy and localized peritoneal controlled trauma in two groups of rats (A, B). Postoperatively, group A received intraperitoneal (ip) treatment by HA (1 mg/kg) for 7 days, and group B, ip saline. The rats were then reoperated upon, and adhesions scored. In vitro studies were performed on postsurgical macrophages and fibroblasts. Fibroblasts were obtained using a single-cell suspension technique by debridement of adhesions. The fibroblasts were cultured for 7 days, and their metabolic activity was assessed by the uptake of [3H]thymidine. Postoperative macrophages were obtained from the peritoneal fluid of the rats operated on, and their effect upon fibroblast [3H]thymidine uptake was studied in mixed cultures. The adhesion score of the HA-treated rats was smaller than the score of the saline-treated group. This observation suggests that ip treatment by HA may decrease adhesion formation in this rat model. [3H]Thymidine uptake by cultured postsurgical fibroblasts was significantly lower in the HA-treated group compared to that of controls. In vitro addition of HA to cultured "saline fibroblast" resulted in a significant decrease in [3H]thymidine uptake, suggesting a direct effect of HA on postsurgical fibroblast metabolism. However, [3H]thymidine uptake by fibroblasts in mixed cultures with macrophages obtained from HA-treated rats was significantly increased. These observations suggest that HA may affect the process of peritoneal healing by direct effect on fibroblast metabolic activity, and indirectly via modification of the macrophage-fibroblast interrelationship.

Inactivation of herpes simplex viruses by nonionic surfactants.

Nonionic surface-active agents possessing ether or amide linkages between the hydrophillic and hydrophobic portions of the molecule rapidly inactivated the infectivity of herpes simplex viruses. The activity stemmed from the ability of nonionic surfactants to dissolve lipid-containing membranes. This was confirmed by observing surfactant destruction of mammalian cell plasma membranes and herpes simplex virus envelopes. Proprietary vaginal contraceptive formulations containing nonionic surfactants also inactivated herpes simplex virus infectivity. This observation suggests that nonionic surfactants in appropriate formulation could effectively prevent herpes simplex virus transmission.

Modulation of the immune response and control of tumour spread by a new synthetic compound.

A small molecular weight biofunctional polymer, NED 137, has been investigated for its anti-neoplastic effect. Through its effect on the immune system, particularly the induction of B cell differentiation to antibody producing cells, this synthetic compound can retard tumour growth and prevent the development of distant metastases. Reactivity to tumour developed following administration of the NED 137. No toxicity has been observed. The polymer NED 137 is now being tested in phase I and phase II clinical trials.

Effects of hyaluronan on models of immediate and delayed hypersensitivity in the rat.

Others have previously shown that superoxide dismutase conjugated with hyaluronan (HA) retains enzymic activity but is non-immunogenic. Whether HA could be widely used to prevent sensitisation to protein/polypeptide therapeutics is not known. In this study we investigated the effects of HA on bovine serum albumin (BSA) and methylated BSA pleural reactions in sensitised rats (active Arthus and delayed hypersensitivity reactions respectively) and on a reverse passive Arthus reaction in which rats received an intravenous injection of rabbit immunoglobulin and intrapleural challenge with goat anti rabbit immunoglobulin. HA suppressed the active Arthus and delayed hypersensitivity models when administered at the time of sensitisation but only the delayed hypersensitivity model at the time of intrapleural challenge. HA did not modulate the reverse passive Arthus reaction. The results show no evidence that simple mixing of HA with antigens masks antigenic determinants. However, HA appeared to have suppressive effects on both antibody and cell-mediated immune reactions. Therefore it may not be necessary to conjugate protein/polypeptide therapeutics to HA in order to prevent immune sensitisation.