Sequence-specific 1H and 15N assignment and secondary structure of transforming growth factor beta3.
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Amino Acid Sequence↗
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Results for “Transforming Growth Factor beta3”
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Proteolytic inactivation of transforming growth factor beta3 by elastase in venous leg ulcers: implications for clinical trials using topically-applied peptide growth factors.
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Growth Substances↗
Enhancement of wound healing by hyperbaric oxygen and transforming growth factor beta3 in a new chronic wound model in aged rabbits.
HYPOTHESIS: Although hyperbaric oxygen (HBO) has been used clinically for 3 decades, there have been few controlled clinical trials. Animal models have not been adequate to test the efficacy of HBO in the treatment of chronic wounds, either by itself or in combination with growth factors. We hypothesize that HBO is as efficacious as a prototype growth factor in improving wound healing in a new animal model of ischemic chronic wounds. DESIGN: Twenty-five aged rabbits and 3 young rabbits had their ears rendered chronically ischemic and ulcers were created down to the level of cartilage. These ulcers were treated in 1 of 3 ways: with HBO, 90 minutes per day, Monday through Friday, for 4 weeks; with transforming growth factor beta(3) at 1 microg/cm(2); or with both modalities combined. Controls were treated with vehicle or hyperbaric room air or both. RESULTS: This model created an aged/ischemic wound that failed to heal spontaneously up to 26 days after wounding (88% reduction compared with aged/nonischemic controls). Hyperbaric oxygen alone and transforming growth factor beta(3) alone both improved healing rate (only 38% reduction in healing compared with aged/nonischemic controls). Combined therapy produced no additional improvement over either modality by itself. CONCLUSIONS: In aged animals, HBO and transforming growth factor beta(3) were equally effective in improving wound healing. Our data suggest that HBO alone may be more effective in the chronic wound than in the acute wound. There was no additive benefit to combining modalities as has been reported in the same wound model in young rabbits.
Aging↗
Transforming growth factor beta3 induces cell death during the first stage of mammary gland involution.
Involution of the mammary gland following weaning is divided into two distinct phases. Initially, milk stasis results in the induction of local factors that cause apoptosis in the alveolar epithelium. Secondly after a prolonged absence of suckling, the consequent decline in circulating lactogenic hormone concentrations initiates remodeling of the mammary gland to the virgin-like state. We have shown that immediately following weaning TGFbeta3 mRNA and protein is rapidly induced in the mammary epithelium and that this precedes the onset of apoptosis. Unilateral inhibition of suckling and hormonal reconstitution experiments showed that TGFbeta3 induction is regulated by milk stasis and not by the circulating hormonal concentration. Directed expression of TGFbeta3 in the alveolar epithelium of lactating mice using a beta-lactoglobulin promoter mobilized SMAD4 translocation to the nucleus and caused apoptosis of these cells, but not tissue remodeling. Transplantation of neonatal mammary tissue derived from TGFbeta3 null mutant mice into syngenic hosts resulted in a significant inhibition of cell death compared to wild-type mice upon milk stasis. These results provide direct evidence that TGFbeta3 is a local mammary factor induced by milk stasis that causes apoptosis in the mammary gland epithelium during involution.
Animals↗
Conformation and self-association of human recombinant transforming growth factor-beta3 in aqueous solutions.
The transforming growth factors-beta (TGF-beta) are important regulatory peptides for cell growth and differentiation with therapeutic potential for wound healing. Among the several TGF-beta isoforms TGF-beta3 has a particularly low solubility at physiological pH and easily forms aggregates. A spectroscopic structural analysis of TGF-beta3 in solution has thus been difficult. In this study, circular dichroism spectroscopy was used to determine the secondary structural elements of TGF-beta3. In addition, the aggregation of TGF-beta3 was investigated systematically as a function of pH and salt concentration using a rapid screening method. Sedimentation equilibrium and sedimentation velocity analysis revealed that TGF-beta3 exists predominantly in two major forms: (i) monomers in solution at low pH and (ii) large precipitating aggregates at physiological pH. Under acidic conditions (pH < 3.8) the protein was not aggregated. At pH approximately 3.9, a monomer right arrow over left arrow dimer equilibrium could be detected that transformed into larger aggregates at pH > 4.1. Aggregation was pronounced in the pH range of 4.3 < pH < 9.8 with the aggregation maximum between pH 6.5 and 8. 5. The aggregation process was accompanied by a structural change of the protein. The CD spectra were characterized by an isodichroic point at 209.5 nm indicating a two-state equilibrium between TGF-beta3 dissolved in solution and aggregated TGF-beta3. Aggregated TGF-beta3 showed a higher beta-sheet content and lower beta-turn and random coil contributions compared with monomeric TGF-beta3. Both the solution structure and the aggregate structure of TGF-beta3 were different from the crystal structure. This was in contrast to TGF-beta2, which showed very similar crystal and solution structures. Under alkaline conditions (pH > 9.8) the turbidity disappeared and a further conformational change was induced. The pH dependence of the TGF-beta3 conformation in solution in the range of 2.3 < pH < 11. 0 was reversible. Aggregation of TGF-beta3 was, furthermore, influenced by the presence of salt. For pH > 3.8 the addition of salt greatly enhanced the tendency to aggregate, even in the very basic domain. Under physiological conditions (pH 7.4, cNaCl = 164 mM) TGF-beta3 has almost the highest tendency to aggregate and will remain in solution only at nanomolar concentrations.
Circular Dichroism↗
An autocrine function for transforming growth factor (TGF)-beta3 in the transformation of atrioventricular canal endocardium into mesenchyme during chick heart development.
Transformation of atrioventricular canal endocardium into invasive mesenchyme is a critical antecedent of cardiac septation and valvulogenesis. Previous studies by Potts et al. (Proc. Natl. Acad. Sci. USA 88, 1510-1520, 1991) showed that treatment of atrioventricular canal endocardial and myocardial cocultures with TGFbeta3 antisense oligodeoxynucleotides blocked mesenchyme formation. Based on this observation, we sought to: (i) identify the target tissue of TGFbeta3 antisense oligos in this transformation bioassay, and (ii) more clearly define the mechanism of TGFbeta3 function in atrioventricular canal mesenchyme formation. In situ hybridization and immunohistochemistry showed little or no TGFbeta3 mRNA or protein in the atrioventricular canal myocardium or endocardium prior to mesenchyme formation (stage 14; paraformaldehyde fixation). However, by stage 18 transforming atrioventricular canal endocardial cells and mesenchyme as well as myocardium were positive for both TGFbeta3 mRNA and protein. In culture bioassays, atrioventricular canal endocardial monolayers pretreated with antisense phosphorothioate oligodeoxynucleotides to TGFbeta3 did not transform into invasive mesenchyme in response to cardiocyte conditioned medium: the subsequent addition of exogenous TGFbeta3 protein relieved this inhibition. Control cultures without pretreatment or those receiving missense oligos generated similar numbers of invasive mesenchyme in response to cardiocyte conditioned medium. Direct addition of TGFbeta3 protein to atrioventricular canal endocardial monolayers in the absence of cardiocyte conditioned medium resulted in loss of cell:cell associations and stimulated cellular hypertrophy, but did not engender invasive mesenchyme formation or alter endocardial proliferation after 24 h of culture. Similar results were obtained with TGFbeta2 protein, either alone or in combination with TGFbeta3. The results of this study indicate that: (i) atrioventricular canal endocardium expresses TGFbeta3 in response to a myocardially derived signal other than TGFbeta3, (ii) atrioventricular canal endocardial TGFbeta3 functions in an autocrine fashion to elicit selected characteristics necessary for cushion tissue formation, and (iii) TGFbeta3 alone or in combination with TGFbeta2 is insufficient to transform atrioventricular canal endocardium into invasive mesenchyme in culture.
Animals↗
An improved recombinant mammalian cell expression system for human transforming growth factor-beta2 and -beta3 preparations.
Transforming growth factor-beta2 and -beta3 (TGF-beta2 and -beta3) are important members of TGF-beta family which play important roles in the growth, maintenance, and repair processes of developing embryos, neonates, and adults. Preparation of large quantities of these two cytokines, which is necessary for structural studies and other applications, has proven to be extremely difficult. We have developed a novel Chinese hamster ovary cell-based expression system for high-level expression and high recovery of recombinant human TGF-beta2 and -beta3. In this system, we used a mammalian expression vector which contains a glutamine synthetase coding region for amplification, together with a modified TGF-beta2 or -beta3 open reading frame for expression. The leader peptide of TGF-beta2 or -beta3 was replaced by that from the V-J2-C region of a mouse immunoglobulin kappa-chain, and a poly-histidine tag was inserted immediately after the leader sequence to facilitate protein purification without changing the mature TGF-beta2 or -beta3 amino acid sequence. In addition, the extreme N-terminal cysteine residue of TGF-beta2 or -beta3 was replaced by a serine residue. The resulting expression constructs produced two stable cell clones expressing 10 mg of TGF-beta2 and 8 mg of TGF-beta3 per liter of spent medium. The purification scheme involved the use of two simple chromatographic steps with a typical yield of 5 mg of TGF-beta2 and 4 mg of TGF-beta3. This method represents a significant improvement over previously published methods and may be applicable to other TGF-beta superfamily members. We further confirmed that latent TGF-beta2 and -beta3 can be activated by proteolysis and glycolysis, which have not been reported before.
Animals↗
Intracranial administration of transforming growth factor-beta3 increases fat oxidation in rats.
The effects of intracranial transforming growth factor (TGF)-beta3 on spontaneous motor activity and energy metabolism were examined in rats. After injection of TGF-beta3 into the cisterna magna of the rat, spontaneous motor activity decreased significantly for 1 h. The intracranial injection of TGF-beta3 produced an immediate decrease in respiratory exchange ratio (RER). No significant changes were observed in energy expenditure. TGF-beta3 induced a significant increase in total fat oxidation and a decrease in total carbohydrate oxidation. Furthermore, the serum substrates associated with fat metabolism were significantly altered in rats injected with TGF-beta3. Both lipoprotein lipase activity in skeletal muscle and the concentration of serum ketone bodies increased, suggesting that the increase in fat oxidation caused by TGF-beta3 may have occurred in the liver and muscle. Intracranial injection of TGF-beta3 appeared to evoke a switch in the energy substrates accessed in energy expenditure. These results suggest that the release of TGF-beta3 in the brain by exercise is a signal for regulating energy consumption.
Animals↗
In vivo attenuation of myointimal hyperplasia using transforming growth factor-beta3 in an interposition graft model.
PURPOSE: To examine if transforming growth factor-beta3 (TGFbeta3) can attenuate the development of para-anastomotic myointimal hyperplasia in an animal model of small-diameter vascular graft failure. METHODS: Under general anesthesia, 10 adult goats underwent bilateral polyurethane interposition graft insertion in the carotid position. Following completion of the anastomoses, each artery received adventitial infiltration of 50 ng of TGFbeta3 around the anastomoses; a placebo was administered to the other side. Postoperatively, each animal received 150 mg of aspirin daily. The arteries were explanted, half at 6 weeks and the remaining 5 at 3 months, for histological examination. RESULTS: Vessel wall thickness surrounding the anastomosis was reduced by 37% in TGFbeta3-treated arteries compared to placebo at 6 weeks and 3 months, principally due to reduced smooth muscle cell proliferation. There was decreased overall luminal loss on angiography. Total collagen content was not significantly different between TGFbeta3 and placebo sides. Further analysis for the subendothelial matrix component collagen type VIII showed decreased levels on the treated side. Total elastin content was reduced on the TGFbeta3-treated side. CONCLUSION: Direct single-dose subadventitial infiltration of TGFbeta3 following insertion of an interposition graft reduces SMC proliferation and elastin content. It would appear that TGFbeta3 holds promise as a prophylaxis against the development of myointimal hyperplasia, the predominant cause of graft failure in peripheral bypass surgery.
Actins↗
Transforming growth factor-beta3 regulates transdifferentiation of medial edge epithelium during palatal fusion and associated degradation of the basement membrane.
Studies on transforming growth factor beta3 (TGF-beta3) deficient mice have shown that TGF-beta3 plays a critical role in palatogenesis. These null mutant mice have clefting of the secondary palate, caused by a defect in the process of fusion of the palatal shelves. A critical step in mammalian palatal fusion is removal of the medial edge epithelial cells from the midline seam and formation of continuous mesenchyme. To determine in more detail the role of TGF-beta3 in palatogenesis, we cultured TGF-beta3 null mutant and wild-type control palatal shelves in an organ culture system. The fate of the medial edge epithelial cells was studied in vitro using vital cell labeling and immunohistochemical techniques. Despite clear adherence, the null mutant palatal shelves did not fuse in vitro, but instead the medial edge epithelial cells survived at the midline position, and the basement membrane was resistant towards degradation. Supplementation of the culture medium with the mature form of TGF-beta3 was able to fully correct the defective fusion in the null mutant specimens. Our results demonstrate that the reason for the defective palatal fusion in TGF-beta3 (-/-) samples is not impaired adhesion. Our data define a specific role for TGF-beta3 in the events that control transdifferentiation of the medial edge epithelial cells including degradation of the underlying basement membrane.
Animals↗
Bone morphogenetic protein-2 acts synergistically with transforming growth factor-beta3 during endothelial-mesenchymal transformation in the developing chick heart.
In the early embryonic heart, endothelial cells in atrioventricular (AV) and outflow tract (OT) regions are transformed into the invasive mesenchymal cells that form endocardial cushion tissue (endothelial-mesenchymal transformation). It has been reported that bone morphogenetic proteins (BMPs) are transcribed in the AV and OT regions of the embryonic mouse heart. We previously reported that transforming growth factor beta 3 (TGFbeta3) triggers the initial phenotypic changes seen in endothelial-mesenchymal transformation. We cloned BMP2 from embryonic chick hearts and examined its functional role during endocardial cushion tissue formation. In situ hybridization showed BMP2 transcripts in the myocardium of the AV and OT regions, but not in endothelial/mesenchymal cells. Antisense oligodeoxynucleotides to BMP2 inhibited mesenchyme formation in AV endocardium cocultured with associated myocardium. This inhibitory effect was reversed by the addition of recombinant BMP2. In cultured AV endothelial monolayers, recombinant BMP2 did not induce any cellular phenotypic changes characteristic of endothelial-mesenchymal transformation. However, BMP2 enhanced the TGFbeta-induced initial phenotypic changes associated with endothelial-mesenchymal transformation. These results suggest that BMP2 1) plays an important role in the formation of endocardial cushion tissue and 2) acts synergistically with TGFbeta3 in the regulation of this developmental event.
Animals↗
Influence of transforming growth factor-beta3 on fibrous capsule formation around microgrooved subcutaneous implants in vivo.
Previous studies have shown that addition of transforming growth factor-beta3 (TGF-beta3) is capable of reducing scar tissue formation in skin defects. Therefore, we examined whether TGF-beta3 can also influence the organization of a fibrous capsule around implants in vivo. For this reason, 24 silicone implants with microgrooves with a groove depth of 1.0 microm and a ridge and groove width of 10.0 microm were made and loaded with human recombinant TGF-beta3 (0, 5, 50, and 250 ng). An in vitro release enzyme-linked immunosorbent assay (ELISA) test was done with another 10 implants to estimate the amount of TGF released from the implants. The implants were inserted subcutaneously in the backs of 6 guinea pigs. Each animal received four implants, which were left in place for 10 weeks. At the end of the implantation time, the implants were retrieved, embedded, and processed for histology. Histomorphometrical measurements were done on the capsule formation and the implant-cell interface quality and quantity. The results showed a fibrous capsule of 15 microm up to 50 microm thickness around all implants. There were no significant differences between the TGF-beta3-loaded implants or the controls. Frequently, inflammatory cells were present in the capsule. The implant-tissue interface was on average between 5 and 15 microm thick and consisted mostly out of one or two layers of macrophages or foreign body giant cells. Statistical analysis again showed no significant differences between the various TGF-beta3-coated implants and controls. Finally, we concluded that a microtextured surface can indeed be used for the release of TGF-beta3. On the other hand, this did not result in major differences in wound healing between implants loaded with 5, 50, or 250 ng of TGF-beta3 and controls.
Animals↗
Transforming growth factor-beta3 protection of epithelial cells from cycle-selective chemotherapy in vitro.
The transforming growth factor-beta (TGF-beta) family of regulatory growth factors can reversibly arrest cell division in the G1 phase of the cell cycle. Previously, TGF-beta3 was shown to protect epithelial cells and hematopoietic cells from cytotoxic damage in vitro and in vivo, and to reduce the severity and duration of oral mucositis induced by 5-fluorouracil (5-FU) in vivo. In the present study, we tested whether TGF-beta3 can protect epithelial cells from a range of chemotherapy drugs with differing mechanisms of action, using the CCL64 cell line as a model system. We report that preincubation of cells with TGF-beta3 for 24 hr resulted in enhanced clonogenicity following exposure to vinblastine, vincristine, etoposide, taxol, ara-C, methotrexate, or 5-FU. Protection was measured in colony-forming assays, which demonstrated that the protected cells could re-enter the cell cycle and undergo multiple rounds of cell division. At high cytotoxic drug concentrations, absolute colony counts were increased for the cultures prearrested by TGF-beta3, as compared with the proliferating control cultures. The effects of TGF-beta3 were reduced for cisplatin and doxorubicin, drugs that are toxic to cells throughout the cell cycle. Thus, TGF-beta3 can effectively reduce the cytotoxicity of anticancer drugs that act predominantly in S or M phase of the cell cycle.
Animals↗
Topical transforming growth factor-beta3 in the prevention or alleviation of chemotherapy-induced oral mucositis in patients with lymphomas or solid tumors.
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.
Adult↗
Physiologically low oxygen concentrations in fetal skin regulate hypoxia-inducible factor 1 and transforming growth factor-beta3.
In the first-trimester mammalian fetus, skin wounds heal with perfect reconstitution of the dermal architecture without scar formation. Understanding environmental molecular regulation in fetal wound healing may reveal scar-limiting therapeutical strategies for the prevention of postnatal scarring wound repair. Therefore, we performed studies on fetal skin oxygenation and skin and wound expression of hypoxia-inducible factor 1alpha (HIF-1alpha) in the sheep model in vivo and performed studies on the potential relevance of HIF-1alpha during wound healing in vitro. Skin oxygen partial pressure levels were hypoxic throughout normal development. In nonscarring fetal skin at gestation day (GD)60, HIF-1alpha could be detected neither in healthy nor in wounded tissue. At GD100, in wounds with minimal scar formation, HIF-1alpha was expressed in fibroblasts and was markedly up-regulated at the wound edge. In scarring fetal wounds at GD120, HIF-1alpha was predominantly expressed in inflammatory cells. Expression of transforming growth factor beta3 (TGF-beta3), a potent antiscarring cytokine, overlapped with HIF-1a expression at GD100. HIF-1alpha-deficient mouse embryonic fibroblasts showed impaired migratory capabilities and demonstrated that TGF-beta3, but not proscarring TGF-beta1, manifests hypoxia- and HIF-1alpha-dependent regulation. In conclusion, HIF-1alpha-dependent regulation of a potent antiscarring cytokine may provide new strategies for antiscarring manipulation of wound healing.
Animals↗
Transforming growth factor-beta3-loaded microtextured membranes for skin regeneration in dermal wounds.
Adverse effects of wound healing, such as excessive scar tissue formation, wound contraction, or nonhealing wounds represent a major clinical issue in today's healthcare. Transforming growth factor (TGF)-beta3 has specifically been implicated in wound healing. Our hypothesis was that local administration of TGF-beta3 to excisional dermal wounds would diminish wound contraction and scar formation. Microtextured wound covers, containing different concentrations of TGF-beta3, were placed onto full-thickness excisional skin wounds in guinea pigs. Tattooed reference marks were used to quantify wound contraction. Sixty-four male guinea pigs in four study groups (5 ng TGF-beta3, 50 ng TGF-beta3, no growth factor, sham wound) were followed for up to 6 weeks. We analyzed 19 different parameters of wound healing. Results showed that, in some instances, the 50-ng TGF-beta3 group gave less contraction, whereas the 5-ng TGF-beta3 group gave more contraction. These differences confirm that TGF-beta3 has an optimum working concentration, and suggest this concentration to be closer to 50 ng than to 5 ng TGF-beta3. However, only very few significant differences occurred, and thus we conclude that the clinical relevance of our findings is negligible. Earlier studies, reporting clinically improved wound healing by TGF-beta3, could therefore not be confirmed by this study.
Actins↗
Preoperative treatment of uterine leiomyomas: clinical findings and expression of transforming growth factor-beta3 and connective tissue growth factor.
OBJECTIVE: To evaluate the clinical features and the expression of transforming growth factor-beta3 (TGF-beta3) and connective tissue growth factor (CTGF) in myometrium and uterine leiomyomas after preoperative treatment with gonadotropin-releasing hormone-analogs (GnRH-a) and tibolone. METHODS: Twenty-three patients received 3.75 mg leuprolide acetate depot for 4 months. Twenty-two patients received the same therapy plus 2.5 mg tibolone daily. Patients underwent uterine surgery after therapy. Twenty-two untreated patients underwent surgery directly. Hematologic tests, bone mineral density (BMD) measurement, and ultrasonographic evaluation of uterine volume were performed before and after treatment. Menorrhagia and pelvic pain were evaluated with a visual analog scale. Hot flushes were recorded in daily diaries. Immunohistochemical expression of TGF-beta3 and CTGF in myometrium and myoma samples was evaluated semiquantitatively. RESULTS: After therapy, hemoglobin and iron levels similarly increased in both groups. BMD significantly decreased only in the GnRH-a group. Uterine volume similarly decreased in both groups. No patient had menorrhagia or pelvic pain at the end of therapy. The number of hot flushes increased after the first month in the GnRH-a group; in the GnRH-a plus tibolone group, it remained constant and was lower. In untreated cases, TGF-beta3 and CTGF smooth muscle cell immunoexpression was lower in myometrium than in leiomyomas. After medical treatment, growth factor immunoexpression remained unchanged in myometrial samples and was reduced in leiomyomas. Endothelial cells showed strong immunopositivity, both in untreated and in treated cases. CONCLUSION: This study focuses on the effects of GnRH-a and tibolone on TGF-beta3 and CTGF expression in myometrium and myomas and supports the hypothesis of a pathogenetic role of these growth factors in uterine fibromatosis.
Adult↗
Phase I study of transforming growth factor-beta3 mouthwashes for prevention of chemotherapy-induced mucositis.
The purpose of this study was to establish the safety and tolerability of recombinant transforming growth factor-beta3 (TGF-beta3; CGP 46614) mouthwashes intended for prevention of chemotherapy-induced mucositis. Local effects were especially analyzed by objective and subjective measurements of mucositis. Secondary aims were analysis of potential systemic exposure and development of anti-TGF-beta3-antibodies. Eleven breast cancer patients received chemotherapy with 1.5 g/m2 cyclophosphamide i.v., 80 mg/m2 epirubicin i.v., and 1.0 g/m2 5-fluorouracil i.v. (n = 8) or 1.6 g/m2 carboplatin i.v., 480 mg/m2 thiotepa i.v., and 6 g/m2 cyclophosphamide i.v. divided over 4 days (n = 3). TGF-beta3 mouthwashes (10 ml; provided by Novartis, Basel, Switzerland) were administered for 4 days, four times a day, starting 1 day before chemotherapy. The dose was escalated in following patients from 25 microg/ml (n = 3) to 50 microg/ml (n = 3) and 100 microg/ml (n = 5). Clinically, the mucosa was scored objectively and according to WHO criteria. The percentage of viable oral epithelial cells was determined by trypan blue dye exclusion. Morphology of cells was assessed in buccal smears. Plasma samples were collected for determination of TGF-beta3 levels and anti-TGF-beta3-antibodies. Adverse events were recorded by the patient in a diary. Mouthwashes with TGF-beta3 were well tolerated. Three patients scored for mucositis > grade 0 (WHO grading criteria). The percentage of viable oral epithelial cells in patients treated with 1.5 g/m2 cyclophosphamide i.v., 80 mg/m2 epirubicin i.v., and 1.0 g/m2 5-fluorouracil i.v. was stable, whereas in patients treated with 1.6 g/m2 carboplatin i.v., 480 mg/m2 thiotepa i.v., and 6 g/m2 cyclophosphamide i.v. divided over 4 days, an increase was observed. The morphology of buccal cells showed a transient shift from mature to immature cells in the first week. Neither systemic absorption of TGF-beta3 nor development of TGF-beta3-antibodies was observed. TGF-beta3 mouthwashes were well tolerated and deserve further study in preventing chemotherapy-induced mucositis.
Administration, Oral↗