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Single versus multiple human-equivalent doses of C. parvum in mice: neutralization of the anti-metastatic effect
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.
Insights
Repeated low doses of Corynebacterium parvum (CP) significantly boosted antibody responses in mice. While single CP doses inhibited tumor metastases, repeated low-dose prophylaxis combined with a single dose negated this anti-metastatic effect.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Corynebacterium parvum (CP) is known to modulate immune responses.
- Understanding optimal dosing strategies for CP is crucial for therapeutic applications.
Purpose of the Study:
- To compare the effects of different Corynebacterium parvum (CP) dosing regimens on immune response and anti-tumor activity in mice.
- To investigate the impact of CP on Lewis tumor metastasis and survival rates.
Main Methods:
- Mice were treated with varying doses of i.v. CP: a murine dose (466 µg), a single low human-equivalent dose (70 µg), and repeated weekly low doses.
- Immune response was assessed by antibody titers against CP.
- Tumor inhibition, metastasis, and survival were evaluated in the context of Lewis tumor implantation and excision.
Main Results:
- All CP treatments increased antibody titers, with repeated doses yielding significantly higher levels.
- Single high or multiple low CP doses caused a 6-fold increase in spleen and liver weight, while single low doses caused a 3-fold increase.
- Single CP doses effectively inhibited pulmonary metastases; repeated low doses starting on Day 0 were not superior.
- Low-dose CP on Day 7 doubled survival time post-tumor excision.
- Low-dose prophylaxis up to 2 weeks before tumor implantation inhibited metastases, but combining it with a single Day 0 dose abrogated this effect, an effect that persisted after a 13-week interval.
Conclusions:
- Repeated low-dose CP administration is superior for stimulating antibody responses compared to single doses.
- While CP demonstrates anti-metastatic properties and enhances survival, a complex interaction exists between prophylactic and therapeutic dosing, leading to potential abrogation of anti-tumor effects.
- The observed neutralization of anti-metastatic effects suggests a need for careful consideration of CP treatment timing and scheduling.