Anti‐tumor effect of combined treatment with thymosin alpha 1 and interleukin‐2 after 5‐fluorouracil in liver metastases from colorectal cancer in rats

Abstract

We studied the effect of combined chemo-immunotherapy, 5-FU followed by thymosin alpha 1 (T alpha 1) and interleukin-2 (IL-2) at low doses, on liver metastases from colorectal cancer, induced by splenic injection of DHD/K12 cells (1,2-dimethylhydrazine-induced colon adenocarcinoma) in syngeneic BDIX rats. The presence of liver metastases was checked by laparotomy 14 days after tumor-cell injection. Evaluable rats were assigned randomly to 5 experimental groups designated as control, 5-FU, IL-2, 5-FU/IL-2 and 5-FU/T alpha 1/IL-2. 5-FU was administered i.v. as a continuous infusion for 7 days by an osmotic device implanted surgically. T alpha 1 and IL-2 were administered for 4 days and repeated after 11 days. Combined chemo-immunotherapy was shown both to significantly reduce the growth of liver metastases and to prevent extra-hepatic spread. 5-FU/T alpha 1/IL-2 also improved survival rate. Combined immunotherapy after 5-FU restored NK activity of the peripheral-blood-mononuclear-cell (PBMC) in tumor and/or 5-FU immunodepressed rats and enhanced PBMC cytotoxic activity against the DHD/K12 autologous cell line. This model was devised to mimic the clinical situation of unresectable liver metastases.

Interleukin-2-activated killer cell activity in colorectal tumor patients: evaluation of in vitro effects by prothymosin?1

“…In addition to our findings, we demonstrated, in a parallel in vitro study, that Pro ~1 also stimulates the antitumor activity of monocytes from colorectal patients (Garbin et al unpublished results). The efficacy of thymic peptides in different chemoimmunoprotocols has been described in only a limited number of studies on experimental colon tumor models and human colon cancer (Chang 1994;Hawkins et al 1994;Rasi et al 1994;Mustacchi et al 1994;Nichols et al 1992;Perrin et al 1994;Iigo et al 1994). Therefore, the Pro cd effect on immunocytotoxic and immunological parameters may be predictive in defining Pro-cd-sensitive colon cancer patient subgroups and this may provide the basis for further applying thymic peptide preparations in selected immunotherapy protocols.…”

“…Different thymic peptide preparations, classified as nonspecific BRM are drugs used for tumor immunotherapy. Both in experimental tumor models (Rasi et al 1994) and in human tumors, including colon cancer, thymic preparations have been reported to increase the efficacy of chemotherapy (Mustacchi et al 1994). However, the efficacy of thymic peptide preparations for immunotherapy of human cancer and their clinical benefit remain controversial (Scher et al 1988).…”

A randomized controlled trial of thymalfasin plus transarterial chemoembolization for unresectable hepatocellular carcinoma

“…Thymalfasin promotes T-cell differentiation, enhances cytokine (IFN-c, IL-2, IL-3) production, and downregulates T-cell apoptosis [15][16][17][18][19][20][21][22][23]. It has been shown to decrease tumor cell growth both in vitro and in vivo [24][25][26][27][28] and has demonstrated therapeutic usefulness in several types of cancer, including non-small cell lung cancer and malignant melanoma [29][30][31]. One phase II study has been completed that examined the efficacy and safety of thymalfasin for the treatment of HCC [32].…”

Activity of Ruboxyl, a Nitroxyl Derivative of Daunorubicin, on Experimental Models of Colorectal Cancer Metastases

“…Rbx was dissolved in sterile saline solution and delivered intravenously with the same system at a constant dose of 24.5 mg/kg for 7 days. Treatment was performed as previously described [11]: briefly, on the day of tumour inoculation, pumps were placed in an abdominal subcutaneous pocket and connected with a polyethylene catheter implanted into the jugular vein using a surgical microscope. At the end of the treatment, all pumps were removed and the delivery system was checked.…”

“…This sequence seems close to the natural course of the human disease. It is therefore a reliable model of clinical CRC metastases and a suitable system to study the antimetastatic activity of different therapies, including prolonged infusion [11].…”