Single versus multiple human-equivalent doses of C. parvum in mice: neutralization of the anti-metastatic effect.

H D Mitcheson,J E Castro,T E Sadler

doi:10.1038/bjc.1980.64

Abstract

The murine dose of i.v. C. parvum (466 microgram) was compared with a single, low, human-equivalent dose of 70 microgram and with repeated weekly low doses. All treatments increased the antibody titre against C. parvum (CP). However, repeated doses stimulated a much higher titre than single doses. In all treated animals spleen weight peaked at 2 weeks and then fell. A single low dose caused a 3-fold increase, a single high dose or multiple low doses a 6-fold increase. Liver weight changes followed a similar pattern. Hepatosplenomegaly was prolonged by multiple doses. The effects of these treatments on Lewis tumour metastases were studied. A single high dose and a single low dose on the day of tumour implantation (Day 0) were equally effective at inhibiting pulmonary metastases. Repeated low doses starting on Day 0 were no more effective than a single dose. The effect of CP on survival after primary-tumour excision on Day 10 was observed. Low dose CP on Day 7 doubled the harmonic mean of survival time. Repeated doses were no more effective than a single dose. Low-dose prophylaxis up to 2 weeks before tumour significantly inhibited metastases. However, when repeated low-dose prophylaxis was combined with a single low dose on Day 0, the anti-metastatic effect was abrogated. This neutralization of the anti-metastatic effect of CP given on Day 0 was found to persist after a 13-week treatment-free interval. Possible mechanisms for this phenomenon are discussed.

Highlights

When repeated low-dose prophylaxis was combined with a single low dose on Day 0, the anti-metastatic effect was abrogated
SYSTEMICALLY INJECTED C. parvum (CP) has considerable anti-tumour properties in rodents (Halpern et al, 1966; Woodruff & Boak, 1966; Smith & Scott, 1972; Proctor et al, 1973; Sadler & Castro, 1976). It is a potent stimulant of the reticulo-endothelial system (RES) (Halpern et al, 1963; Adlam & Scott, 1973) and non-specific activation of macrophages is generally regarded as mediating the anti-tumour effect
Toxicity.-Mice given a high dose of CP became very ill for several hours with erect fur, dyspnoea and a slow, staggering gait

Summary

Introduction

When repeated low-dose prophylaxis was combined with a single low dose on Day 0, the anti-metastatic effect was abrogated This neutralization of the anti-metastatic effect of CP given on Day 0 was found to persist after a 13-week treatment-free interval. Cancer patients have been treated with systemic CP (Israel et al, 1975; Takita & Moayeri, 1976; Sarna et al, 1977) but there is still no convincing evidence of a beneficial antitumour response This difference between man and rodents may be due to the dose of the vaccine since, owing to the severity of the side-effects, the human dose, when related to surface area, is much lower than the murine dose (Scott & Warner, 1976). We compared our usual mouse dose (a single injection of 466 /tg) with a single low, human-equivalent dose (70 jig) and with repeated humanequivalent doses

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