Affiliations of authors: V. Pierrefite-Carle, A. Gavelli, N. Brossette, B. Rossi, Unité INSERM 364, IFR 50, Faculté de Médecine, Nice, France; P. Baqué, D. Benchimol, A. Bourgeon, Service de Chirurgie Abdominale et Thoracique, Hôpital l'Archet II, Nice; P. Staccini, Biostatistiques et Informatique Médicale, Faculté de Médecine, Nice.
Correspondence to: Valérie Pierrefite-Carle, Ph.D., Unité INSERM 364, Faculté de Médecine, Avenue de Valombrose, 06107 Nice cédex 2, France (e-mail: pierrefi{at}unice.fr).
We recently reported that suicide vaccination by subcapsular injection of autologous tumor cells expressing the bacterial gene cytosine deaminase followed by 5-fluorocytosine (5-FC) treatment significantly increased the survival of rats carrying a single liver metastasis (1). We wish to supplement these data with results concerning the effect of suicide vaccination in a polymetastatic liver model.
DHD/K12/PROb (PROb) rat colon carcinoma cells (20.0 x 106) (2) were injected in the portal veins of 27 male BDIX rats (IFFA CREDO, L'Arbresle, France) to generate experimental disseminated liver metastasis. Five days later, the presence of multiple liver tumors was confirmed surgically, and the animals were randomly assigned to one of three groups. In the control group (n = 11), animals were left untreated. In the first experimental group (n = 10), 1.5 x 106 PROb cells expressing the cytosine deaminase gene (PRObCD cells) (1) were injected subcapsularly in the left lobe. To explore if homing of circulating suicide cells to pre-existing tumors might improve the vaccination efficiency, we injected 10.0 x 106 PRObCD cells into the portal veins of a second experimental group (n = 6) of animals. After 24 hours, rats of the experimental groups received three daily (7 days per week) intraperitoneal injections of 5-FC (Produits Roche, Fontenay Sous Bois, France) (800 mg/kg of body weight) for 30 days, followed by daily 5-FC injections (5 days per week) for 3 months. 5-FC was dissolved in saline at 15 mg/mL. All of the surgical procedures and the care given to the animals were in accordance with institutional guidelines.
Survival curves for each group are presented in Fig. 1. All control
animals died between 47 and 157 days, after the injection of the PROb cells (median = 95
days). In the subcapsular vaccination group, the median survival of vaccinated animals was
increased by 58% (150 versus 95 days), and four of 10 rats were still alive at day 210.
According to the log-rank test, this vaccination increased the survival of these animals (two-sided
P = .01). For the second experimental group (intraportal vaccination), the
median survival was 122 days, and one of six animals was still alive at day 210 (two-sided P = .04). Despite the fact that this latter result was not statistically significant (P
.025 used as the criterion of statistical significance), it is noteworthy that intraportal
injection of a large number of autologous suicide tumor cells did not further stimulate disease
progression. In all groups, dead animals generally exhibited advanced peritoneal carcinomatosis,
and some of them had pulmonary metastasis (control group = 45%; subcapsular
vaccination group = 16%; portal vein vaccination group = 20%).
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NOTES
V. Pierrefite-Carle and A. Gavelli contributed equally to this work.
Supported by the Institut National de la Santé et de la Recherche Médicale, Association pour la Recherche sur le Cancer, and Institut de Recherche sur les Maladies de l'Appareil Digestif (IRMAD).
We are indebted to M. C. Saint Paul and the Anatomo-pathology Department of Hôpital Pasteur (Nice). We thank Produits Roche for supplying us with 5-FC.
REFERENCES
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Pierrefite-Carle V, Baque P, Gavelli A, Mala M, Chazal M,
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4
Gnant MF, Puhlmann M, Alexander HR Jr, Bartlett DL. Systemic
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Gnant MFX, Noll LA, Irvine KR, Puhlmann M, Terrill RE,
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