The low bone marrow toxicity of high dose alkylating agents when given in combination with whole body hyperthermia (WBH) may be explained in part by the parallel induction of the granulocyte colony stimulating factor. Since transforming growth factor beta (TGF beta) is known to act synergistically with colony stimulating factors, we performed studies of TGF beta expression under WBH in 12 patients with histologically confirmed metastatic sarcoma. Each patient was given ifosfamide, carboplatin, and etoposide combined with WBH (41.8 degrees C, 1 h). Plasma specimens far determination of TGF beta levels were taken prior to WBH and at different time points after start of WBH. Immunoreactive TGF beta 1 and TGF beta 2 were measured by ELISA. Follow-up revealed a significant increase in TGF beta 1 and TGF beta 2 in 9 of 12 patients, starting 2 h after begin of WBH and peaking 10 h later. The mean value for TGF beta 1 prior to therapy was 3.3 ng/ml (range: 0.9-7.3 ng/ml), rising after 12 h to 5.3 ng/ml (range: 2.8-11,5 ng/ml) (p<0.05). The values for TGF beta 2 were 3.1 ng/ml (range: 1.9-4.1 ng/ml) and 3.9 ng/ml (range: 3.2-4.5 ng/ml) (p<0.05), respectively, Both TGF beta 1 and TGF beta 2 had to be activated in vitro by acidification, Initial TGF beta 1 and TGF beta 2 levels did not differ from those in healthy controls. Collectively, our data indicate enhanced TGF beta 1 and TGF beta 2 expression under WBH and support the thesis that TGF beta is a myeoloprotective factor because it stimulates granulopoiesis. The transient growth arrest of very early stem cells by TGF beta may be an additional factor contributing to the low myelotoxicity of alkylating agents when given under WBH.

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