Effects of all-trans retinoic acid on tumor recurrence and metastasis

Abstract

Objective: all-trans-retinoic acid (ATRA) promotes cell differentiation. We have studied its effect on the local recurrence and metastatic spreading of an experimental rhabdomyosarcoma in rats.Design: syngenic rhabdomyosarcoma cells (S4MH) were inoculated s.c. in male WAG/RijCrl rats. After 25 days tumors were excised and a 40% hepatectomy was performed for all animals. Ten days later the rats were sacrificed and a thorough necropsy was performed. The animals were randomly allocated to receive daily doses of ATRA (5 mg/kg, i.p.) or its solvent (Clinoleic ® /ethanol 90/10), starting three days before surgery until the end of the experiment.Results: ATRA reduced the incidence of local recurrence from 70 to 33% (p < 0.05), but the tumor size was not altered (1.8 vs. 2.0 cc). Regarding inguinal metastasis, there was a sixfold decrease (0.2 vs. 1.2 cc; p < 0.05) in mean tumor volume, although the rate of this proliferation increased sharply (86 vs. 29%; p < 0.05) for treated animals. The volume of the retroperitoneal tumor masses also decreased with ATRA (0.7 vs. 5.1 cc; p < 0.05), but the difference in rate was not significant (71 vs. 67%). Lung metastases, which were present in 100% of control animals, were found in only 33% of treated rats, while the mean number of metastatic foci dropped from 26.7 to 5.7 (p < 0.05).Conclusion: protocols including retinoid administration prior to and following primary tumor excision could help in controlling both recurrence and metastatic progression in surgically treated rhabdomyosarcoma.Key words: Rat. Rhabdomyosarcoma. Recurrence. Metastasis. All-trans-retinoic acid. García-Alonso I, Palomares T, Alonso INTRODUCTIONOver the past decade, remarkable progress has been made in antineoplastic therapy, with surgery still in the forefront as the main curative approach. However, recurrence of disease following tumor resection remains a major problem, not only because of failed local control but also because of the effect of surgery on the distant proliferation of disease, thus reducing patient quality of life and survival (1).While tumor recurrence depends to a great extent on the radicality of surgery, it can also be induced by biological responses initiated following tissue aggression as implied by the operation itself. Indeed, in an experimental carcinogenesis model, researchers observed that the rate of colon tumor development following a carcinogen was much higher within healing anastomoses in the colon (2).Surgery, it must be remembered, triggers local release of multiple growth factors (GF) that are responsible for wound healing, but which may also act as paracrine factors giving tumor cells the signal they require to divide and proliferate (3). Such factors include beta fibroblast proliferation-stimulating GF (FGFb), platelet-derived growth factor (PDGF), hepatocyte growth factor (HGF), and others (4-6). It is important therefore to design combined treatments that will inhibit residual tumor cell proliferation following surgery, without impairment of the healing process.Today ...

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“…[20]. Similar data exist for other sarcomas [21][22][23][24]. Improved survival with acceptable toxicity was found for the maximum tolerated dose of 160 mg/m 2 /day of oral 13-cisretinoic acid (isotretinoin) given for 14 days, followed by a 14-day resting period in children with neuroblastoma treated after autologous bone marrow transplant [25,26].…”

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“…For example, dietary retinyl palmitate decreased malignant melanoma metastasis in mice [3]. All-trans-retinoic acid (ATRA) decreased breast cancer [4], gastric cancer [5], and colon cancer invasion [6] in vitro and rhabdomyosarcoma metastasis in rats [7]. Also, retinol decreased hepatic metastasis in a hamster model of pancreatic ductal carcinoma [8].…”