<i>Corynebacterium parvu</i><i>m</i>, but not BCG, Induces Elevations in Plasma Proteinase Activity Similar to Those Observed in Tumor-Bearing Mice

Abstract

Intraperitoneal administration of Corynebacterium parvum to BALB/c, C57B1/6 or C3H/HeJ mice lead to the induction of elevated levels of neutral proteinase activity (¹²⁵I-caseinolytic activity) similar to those observed previously in animals bearing the BCL₁ leukemia or the B16-F10 melanoma. Enhanced activity reached a peak at 7–14 days postin-jection of the C. parvum and then gradually returned to normal levels by 20–25 days postin-jection. Increased plasma proteinase activity could be induced by C. parvum whole cells or the pyridine extract residue of C. parvum but not by BCG or the pyridine extract of C. parvum. BCG did not interfere with the induction of elevated levels of activity by C. parvum. Splenectomized animals responded the same as normal mice indicating that the splenomegaly accompanying the onset of increased plasma proteinase activity was not responsible for the changes. Administration of C. parvum via a subcutaneous site rather than intraperitoneally failed to induce systemic changes in proteinase activity while still inducing splenomegaly. Treatment of animals with C. parvum before or after transplantation of the BCL₁ leukemia or the B16-F10 melanoma failed to alter the course of the disease or enhance the increased proteinase activity of plasma over that observed in plasma from animals bearing tumors alone. These observations support the hypothesis that the induction of disturbances in plasma proteinase activity in tumor-bearing animals is due to alterations in host systems and that C. parvum, in contrast to BCG, contains components which can mimic the effect of some tumors on host systems.

Differences between Beige and bg/+ Mice in the Disruption of Plasma Proteinase Regulation in the Tumor-Bearing State or following <i>Corynebacterium parvum</i> Treatment

“…The cells were grown in vitro, washed three times with medium (RPMI-1640, Flow Laboratories), and then 10s cells were injected into a subcutaneous site on the flank. The pyridine extract residue of C. parvum (CP-PER) was obtained from RIBI Immuno Chemicals (Hamilton, Mont., USA) and was the same lot of material used previously [13,15]. The material was resuspended in sterile phosphate-buffered saline (PBS; pH 7.4) immediately prior to use.…”

“…The material was resuspended in sterile phosphate-buffered saline (PBS; pH 7.4) immediately prior to use. Animals received an intraperitoneal injection of 2.5 mg CP-PER, a dose previously demonstrated to yield maxi mal disruption of plasma proteinase homeostasis [15].…”

“…The neutral proteinase activity in triplicate aliquots of plasma was determined as described previously [10][11][12][13][14][15] using l25I-casein. Brief ly, 25 pi of citrated plasma from each mouse was incubated with 75-100 pg l25I-casein (~ 150,000 cpm pg) for 3.5 h at 37 °C.…”

“…In addition, the induction of elevation in plasma protein ase activity appeared to be regulated by host factors, since transplantation of tumors to an intraocular site did not result in disruption of homeostasis [12]. The induction of ele vated levels of plasma proteinase activity could not be inhibited by corticosteroids [13] or indomethacin [14], Further indica tion that the disruption of plasma proteinase regulation involved host factors was the finding that treatment of mice with Corynebacterium parvum, but not bacille Calmette Guérin, led to elevation in plasma protein ase activity to levels comparable to those observed in the tumor-bearing state [15], In addition, it was found that treatment of tumor-bearing mice, exhibiting elevated plasma proteinase activity, with C. parvum did not lead to further elevation in plasma activity [15], and induction of changes by C. parvum could not be inhibited by high-dose corticosteroids [13]. Therefore, several par allels between the changes induced by C. par vum and those induced by the tumors were detected.…”

Systemic toxicity of non-cell corynebacterium parvum (CP) in monkeys

“…It can elevate the immune function via multifaceted actions, including activating macrophages, regulating T cell immune responses and promoting haematopoietic stem cells to differentiate into monocytes (Thatcher et al, 1977;Rossol et al, 1990;Matsui et al, 1997). Its therapeutic effect is comparable in some respects to BCG in mice and human (Lau et al, 1986;Hart, 1987;Lipton et al, 1991). However, many investigations have demonstrated that CP-treated mice could develop splenic intumescences and intrahepatic granulomas (Riveros-Moreno et al, 1979;Tsuji et al, 1999).…”