Topical Transforming Growth Factor-β3 in the Prevention or Alleviation of Chemotherapy-Induced Oral Mucositis in Patients with Lymphomas or Solid Tumors

Abstract

Transforming growth factor (TGF)-beta3 has been hypothesized to prevent or alleviate oral mucositis (OM) in cancer patients receiving high-dose chemotherapy (CT). Two double-blind, placebo-controlled, multicenter, phase II studies of TGF-beta3 were initiated in the United States, Europe, and Argentina in patients with lymphomas or solid tumors who were receiving highly stomatotoxic CT regimens. Patients were to apply 10-mL mouthwash applications of TGF-beta3 (25 microg/mL) or placebo four times daily (or twice daily) 1 day before and all days during CT. The patients were subsequently evaluated for OM incidence, severity, and duration using National Institute of Cancer Common Toxicity Criteria (NCI-CTC) criteria and an objective scoring system (1). After the start of the trials, negative results from new preclinical studies suggesting suboptimal formulation and/or dosing led to an interim analysis of the ongoing clinical trials. One hundred fifty-two patients from the combined studies were included in the interim analysis, with 116 patients on the TGF-beta3 four times daily and placebo arms. Most (72%) patients had breast cancer, 22% had lymphomas, and 6% had other solid tumors. Although 98% (149 of 152) of patients experienced adverse events, only 14% (22 of 152) experienced events that were judged as possibly or probably related to the study drug (primarily gastrointestinal symptoms). No clinically relevant differences were seen between the treatment and placebo arms regarding safety, nor was there evidence for systemic absorption of TGF-beta3. Finally, there was no advantage of TGF-beta3 treatment regarding the incidence (TGF-beta3 four times daily versus placebo [46% versus 47%]), onset, or duration of NCI-CTC grade 3 or 4 OM. For this dose, formulation, regimen. and patient population, TGF-beta3 was not effective in the prevention or alleviation of CT-induced OM.

Systematic review of cytokines and growth factors for the management of oral mucositis in cancer patients

“…TGF-β mouthwashes or enriched food were not effective to reduce oral mucositis in the used formulations [80][81][82]. A mouthwash with bovine milk-derived whey growth factors (PV-701) was well tolerated, and as compared to historical controls, the severity as well as the duration of oral mucositis seemed to be decreased in autologous HSCT recipients [83].…”

TGF-β Signal Transduction in Oro-facial Health and Non-malignant Disease (Part I)

“…Topical application of TGF-␤3 prior to chemotherapy with 5-Fluorouracil in hamsters resulted in a significant reduction in oral mucositis (Sonis et al, 1997). Despite these early encouraging results, however, a doubleblind, placebo-controlled, multi-center phase II clinical trial has shown that TGF-␤3 is not effective in the prevention or alleviation of chemotherapy-induced oral mucositis (Foncuberta et al, 2001). In chronic wounds, high levels of proteases causing cytokine breakdown, the presence of underlying systemic disease, and the lack of vascularity at the wound site, together with the placebo effect of any clinical trial, could contribute to these clinical findings.…”

Medical Applications of Transforming Growth Factor-

“…68,69 In a hamster model of chemotherapy-induced oral mucositis, application of TGF-β3 reduces the severity and duration of the resulting mucositis, 70 and clinical trials of TGF-β3 to treat this condition are underway. 71 TGF-β has also been shown to accelerate the repair of bone defects. In canine models, both TGF-β1 and TGF-β2 have been effective in increasing bone formation when applied to defects in the alveolar ridge and in the humerus, respectively.…”

“…109 This proteolytic degradation of ligand may have contributed to the inefficacy of topical TGF-β3 in treating chemotherapy-induced oral mucositis in patients with lymphomas and solid tumors. 71 In spite of these problems, some current clinical modalities may be acting by decreasing TGF-β signaling. The success of angiotensin-converting-enzyme inhibitors in treating diabetic nephropathy, interferon-α in treating hepatic fibrosis, azathioprine and prednisone in treating autoimmune hepatitis, and interferon-γ in treating pulmonary fibrosis is due, in part, to the ability of these agents to reduce serum levels of TGF-β.…”