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FJ
EXPRESS SUMMARY ARTICLE The Full-length version of this article is also available, published online July 18, 2003 as doi:10.1096/fj.02-1201fje. |
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Departments of
* Medical Biochemistry and Microbiology, and
Medical Cell Biology, Section of Physiology, Uppsala University, BMC, Uppsala, Sweden;
Department of Physiology, University of Bergen, Bergen, Norway; and
Department of Radiology, University Hospital, Uppsala, Sweden
2Correspondence: Department of Medical Biochemistry and Microbiology, Uppsala University, BMC, Box 582, SE-751 23 Uppsala, Sweden. E-mail: Kristofer.Rubin{at}imbim.uu.se
SPECIFIC AIMS
We tested the hypothesis that lowering pathologically elevated tumor interstitial fluid pressure (TIFP), a characteristic of carcinomas, augments the efficacy of chemotherapy. Furthermore, we investigated potential mechanisms for the increased transport of solutes into the interstitium of experimental carcinoma during the time when TIFP is reduced.
PRINCIPAL FINDINGS
1. Acute reduction of TIFP by prostaglandin E1 (PGE1) enhanced the anti-tumor activity of 5-fluorouracil (5-FU)
Instillment of PGE1 transiently lowers TIFP and increases capillary-to-interstitium transport of 51Cr-EDTA in a syngeneic rat colonic carcinoma (PROb) and in dimethyl-benz-anthracene-induced rat mammary carcinoma (DMBA). TIFP reaches a minimum 10–15 min after treatment with PGE1 and returns to its initial value within 60 min in both carcinoma models. PGE1 lowers IFP and generates the formation of edema in normal rat dermis, effects that most likely involve a decrease in the tension exerted by connective tissue cells on the extracellular matrix–fiber network. Previously, we observed an increase in total tissue water in PROb carcinoma treated with PGE1, suggesting that an interstitial edema was formed. Here, we report that reducing TIFP by instilling PGE1 around PROb carcinomas increases capillary-to-interstitium transport of [3H]5-FU (Fig. 1
A). Furthermore, we show that reducing TIFP by PGE1 augments the anti-tumor effects of 5-FU in PROb and DMBA tumors (Fig. 1C-E
). The relation between TIFP and 5-FU efficacy was demonstrated using an experimental design based on the short plasma half-life of 5-FU combined with administering 5-FU at a time point before or after lowering TIFP by PGE1. Growth of PROb and DMBA carcinomas was significantly retarded only when 5-FU was administered while TIFP was reduced. The combination of PGE1 and 5-FU had a maximal effect when 5-FU reached a maximal level in plasma at the same time that TIFP reached the minimum (Fig. 1B, C
). If 5-FU and PGE1 were administered at sufficiently separated time points, the combination therapy lacked significant anti-tumor activity in PROb (Fig. 1D
) and DMBA (Fig. 1E
) carcinomas. This marked time-dependence strongly suggests that PGE1 exerted its potentiation of 5-FU efficacy by lowering TIFP. Furthermore, this dependence demonstrates that PGE1 did not increase the sensitivity of carcinoma cells to 5-FU. Effective tumor growth retardation was associated with an increase in apoptosis in PROb carcinoma and with a decrease in the density of carcinoma cells, as identified by cytokeratin expression.
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2. Reduction of TIFP by PGE1 did not change tumor blood flow, blood volume, or protein extravasation and was not dependent on blood pressure
To investigate potential physiological mechanisms for the increased transport of 5-FU into the tumor interstitium after PGE1 administration, the effects of PGE1 on blood volume, blood flow, and protein extravasation in PROb tumors were studied. Blood volume, as determined by magnetic resonance (MR) imaging, was not changed in tumors treated with PGE1 compared with controls that only received vehicle (PBS; Fig. 2
A). Furthermore, the pattern of distribution of the contrast agent was similar in tumors treated with PGE1 and PBS (Fig. 2B
). Neither blood flow, determined by radiolabeled microspheres (Fig. 2C
), nor extravasation of HSA, labeled with radioactive iodine (Fig. 2D
), was affected by the instillment of PGE1. The latter finding indicates that treatment with PGE1 did not increase plasma protein leakage from blood-to-tumor interstitium. Lowering of blood pressure by continuous i.v. infusion of sodium nitroprusside did not affect the TIFP in PROb carcinomas (Fig. 2E
).
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3. Effective tumor growth retardation after treatment with PGE1 and 5-FU was not a result of changes in tumor vascularity or of an induction of an immune response
The vessel density in the tumor-viable zone was significantly decreased in tumors from all groups of animals receiving 5-FU. There was, however, no significant difference in vessel density between tumors that received 5-FU alone or PGE1 and 5-FU injected outside the time period during which TIFP was low compared with the carcinomas that had received the effective combination of PGE1 and 5-FU, in spite of carcinoma growth retardation in the latter. Vessel coverage by pericytes and smooth muscle cells was qualitatively similar in carcinomas subjected to the various treatment regimes. Our results thus indicate that the potentiated efficacy of the combined PGE1 and 5-FU treatment was not a result of inhibition of angiogenesis or major changes in tumor vasculature.
We examined the possibility that carcinoma growth retardation in the syngeneic PROb model may be partly attributed to immunomodulatory effects of PGE1. Analysis of the cellular composition of the tumor-viable zone did not, however, reveal any significant differences in the density and distribution of T-lymphocytes, macrophages, or granulocytes in the tumors from any of the animal groups. The absence of major histocompatibility complex class II antigen expression in tumor tissues further strengthens the concept that the combination treatment did not induce an immune response in the carcinomas.
CONCLUSIONS AND SIGNIFICANCE
Reduced TIFP enabled increased delivery and treatment efficacy of the low molecular weight cytostatic 5-FU in experimental carcinomas (Fig. 3
). The potentiated effect was evident as carcinoma growth retardation and changes in tumor morphology and was not a result of immune responses or of changes in vasculature. The study emphasizes the importance of convective transport of low molecular weight water-soluble chemotherapeutic agents into carcinoma interstitium after reducing TIFP. This concept of lowering TIFP should be taken into account for future clinical trial design using combinations of conventional cytostatics with various inhibitors of, e.g., tyrosine kinases, cyclooxygenase-2, or endothelins. The present study highlights the important role of TIFP for the efficacy of chemotherapy of solid malignancies.
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FOOTNOTES
1 To read the full text of this article, go to http://www.fasebj.org/cgi/doi/10.1096/fj.02-1201fje; doi: 10.1096/fj.02-1201fje 
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) PGE1 followed 1 min later by 5-FU; (
) PGE1 followed by PBS; and (•) PBS followed by 5-FU. At all time points after day 3, the tumor size increase in the group receiving PGE1, followed 1 min later by 5-FU, was significantly lower than the two control groups. D, E) Size increase of PROb- and DMBA-induced tumors at day 10 of the experiment (mean±SEM). 5-FU was administered i.p. at various time points before PGE1 instillment (–) or after PGE1 instillment. The cytostatic was given at predetermined, low doses, which lacked a significant effect on growth in PROb and DMBA tumors.
