Search

Background. Systemic treatment of malignancies with high doses of tumour necrosis factor-alpha (TNF alpha) has an anticancer effect, but also serious side effects. The aim of the present study was to elucidate the effects of local TNF alpha administration alone or in combination with chemotherapy on tumour stroma structure and physiology in di-methyl-benz-anthracene (DMBA)-induced mammary carcinomas in rats. Methods. TNF alpha (500 ng/mL in a volume of 5 mu L) was given s.c. around the carcinoma and 5-fluorouracil (5-FU) (1.5 mg/kg, volume of 0.2 mL) was given i.p on days 1, 4, 7 and 10. Results. Treatment with TNF alpha resulted in a significant reduction of tumour interstitial fluid pressure (TIFP: 75-87 %, p<0.02-0.001), as well as in the number of tumour-infiltrating macrophages, extracellular volume (ECV) and collagen fibril density in carcinoma. In addition, pH was lowered in tumours treated with TNF alpha, suggesting decreased aerobic metabolism. Treatment with TNF alpha, however, had no effect on tumour growth, arterial blood pressure, tumour vessel density, plasma volume or body weight. Concentrations of locally produced VEGF and IL-1 beta in carcinoma interstitial fluid or in serum were not affected by TNF alpha. The study demonstrated that these cytokines are produced locally in the tumour. Furthermore, TNF alpha had no effect on efficacy of treatment with 5-FU. Conclusions: Locally administered TNF alpha did not affect DMBA-induced mammary tumour growth or vasculature, but reduced inflammation and ECM structure, suggesting the latter to be of importance in the observed reduction in TIFP.

Objective. To evaluate the effects of dexamethasone (DXM) alone or in combination with 5-fluorouracil (5-FU) on dimethyl-alpha-benzanthracene (DMBA)-induced mammary tumors in rats. Material and methods. Female Sprague-Dawley rats were divided into 4 groups receiving: 1) saline (controls), 2) DXM (3 mg/kg), 3) 5-FU (1.5 mg/kg) and 4) DXM and 5-FU combined. The drugs were given i.p. every day for 4 days. Interstitial fluid pressure (Pif) and tumor growth were determined in all tumors on days 1, 5 and 7 using the "wick-in-the needle'' technique and by external size measurements, respectively. Vessel density and inflammatory cell infiltration of tumor tissue were analyzed by immunohistochemistry. Results. DXM treatment significantly retarded tumor growth and reduced Pif. Treatment with a combination of DXM and 5-FU reduced tumor size significantly more than any of the agents alone (p < 0.01 - 0.001). Enhanced uptake of 5-FU by DXM treatment was demonstrated by microdialysis. There were no differences in the density of CD31-positive vessels after DXM or 5-FU treatment, but inflammatory cell infiltration of tumor tissue was significantly reduced after DXM treatment. Conclusions. Our data suggest that DXM may be beneficial as an adjuvant to chemotherapy in the treatment of mammary cancer by increasing the uptake of 5-FU in the tumor.

A pathologically elevated interstitial fluid pressure (IFP) is a characteristic of both clinical and experimental carcinoma. The soluble TGF-beta receptor type II-murine Fc:IgG2A chimeric protein (Fc:TbetaRII) lowers IFP in the KAT-4 experimental model for anaplastic thyroid carcinoma. Analyses of messenger RNA (mRNA) expressions by Affymetrix microarrays and RNase protection assays, as well as of protein expressions identified tumor macrophages as targets for Fc:TbetaRII. Treatment with Fc:TbetaRII reduced albumin extravasation, increased coverage of alpha-smooth muscle actin-positive cells and reduced expression of NG2, a marker of activated pericytes, in KAT-4 carcinoma blood vessels. Specific inhibition of interleukin-1 (IL-1), a major cytokine produced by activated macrophages, lowered carcinoma IFP to a similar degree as Fc:TbetaRII but had no significant effect on the parameters of blood vessel maturation. Neither Fc:TbetaRII nor inhibition of IL-1 changed blood vessel density. Finally, pretreatment of KAT-4 carcinomas with Fc:TbetaRII increased the antitumor efficacy of doxorubicin. Our data emphasize a potential role of tumor macrophages in carcinoma physiology and identify these cells as potential stromal targets for treatment aimed to improve efficacy of chemotherapy.

Chemotherapy of solid tumors is presently largely ineffective at dosage levels that are compatible with survival of the patient. Here, it is argued that a condition of raised interstitial fluid pressure (IFP) that can be observed in many tumors is a major factor in preventing optimal access of systemically administered chemotherapeutic agents. Using prostaglandin E1-methyl ester (PGE1), which is known transiently to reduce IFP, it was shown that 5-fluorouracil (5-FU) caused significant growth inhibition on two experimental tumors in rats but only after administration of PGE1. Furthermore, timing experiments showed that only in the period in which IFP is reduced did 5-FU have an antitumor effect. These experiments uniquely demonstrate a clear and, according to the starting hypothesis, logical, synergistic effect of PGE1 and 5-FU that offers hope for better treatment of many tumors in which raised IFP is likely to be inhibiting optimal results with water-soluble cancer chemotherapeutic agents.