M. S. Anscher, I. R. Crocker, and R. L. Jirtle. Transforming growth factor-beta 1 expression in irradiated liver. Radiat Res 122 (1):77-85, 1990.

The expression of transforming growth factor-beta 1 (TGF-beta 1) in the liver of irradiated rats was increased in a dose-dependent fashion 9 months after irradiation. Expression of TGF-beta 1 was confined primarily to hepatocytes in the pericentral region of the liver, and the percentage of hepatocytes strongly positive for TGF-beta 1 was significantly correlated with the extent of fibrosis. We further showed that a localized injection of TGF-beta 1 into normal rat liver elicited a strong fibrotic reaction at the injection site. These results suggest that the increased hepatic concentration of TGF-beta 1 in response to radiation injury may be important in the pathogenesis of radiation hepatitis. TGF-beta 1 was also found to be present at a significantly higher concentration in unirradiated human hepatocytes than in normal rat hepatocytes, implying that the propensity for humans to develop radiation hepatitis may result in part from the elevated levels of TGF-beta 1 normally found in human liver

M. S. Anscher, L. B. Marks, T. D. Shafman, R. Clough, H. Huang, A. Tisch, M. Munley, J. E. Herndon, J. Garst, J. Crawford, and R. L. Jirtle. Risk of long-term complications after TFG-beta1-guided very-high-dose thoracic radiotherapy. Int J Radiat Oncol Biol Phys 56 (4):988-995, 2003.

PURPOSE: To report the incidence of late complications in long-term survivors of very-high-dose thoracic radiotherapy (RT) treated on a prospective clinical trial. METHODS AND MATERIALS: Patients with locally advanced or medically inoperable non-small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved lymph nodes to a dose of 73.6 Gy at 1.6 Gy twice daily. If the plasma transforming growth factor-beta1 (TGF-beta1) level was normal after 73.6 Gy, additional twice-daily RT was delivered to successively higher total doses until the maximal tolerated dose was reached. Patients within a given dose level were followed for 6 months before escalation to the next dose level was permitted. Late complications were defined according to Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: Thirty-eight patients were enrolled between 1996 and 1999. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGF-beta1 levels. Fourteen patients received dose escalation (80 Gy in 8; 86.4 Gy in 6). Grade 3 or greater late complications occurred in 4 of 24, 1 of 8, and 2 of 6 patients treated to 73.6, 80, and 86.4 Gy, respectively. The corresponding patient numbers with late Grade 4-5 toxicity were 3 of 24, 0 of 6, and 0 of 8. Overall, 7 (18%) of the 38 patients developed Grade 3-5 late toxicity. Nonpulmonary complications predominated (4 of 7). Five (71%) of seven serious complications developed within 11 months after RT; however, the remaining two complications (29%) occurred very late (at 43 and 62 months). The 5-year actuarial risk of late Grade 3-5 complications was 33%. CONCLUSION: Long-term survivors of very-high-dose RT for non-small-cell lung cancer have a significant risk of severe treatment-related complications. At these high dose levels, the predominant toxicity may no longer be pulmonary. All Grade 4-5 complications occurred in patients whose dose was limited to 73.6 Gy because of a persistently elevated TGF-beta1. Thus, persistently elevated plasma TGF-beta1 levels toward the end of RT may identify patients at greatest risk of severe complications

Barcellos-Hoff. Latency and activation in the control of TGF-beta. J Mammary Gland Biol Neoplasia 1 (4):353-363, 1996.

The biological activity of the transforming growth factor-beta’s (TGF-beta) is tightly controlled by their persistance in the extracellular compartment as latent complexes. Each of the three mammalian isoform genes encodes a product that is cleaved intracellularly to form two polypeptides, each of which dimerizes. Mature TGF-beta, a 24 kD homodimer, is noncovalently associated with the 80 kD latency-associated peptide (LAP). LAP is a fundamental component of TGF-beta that is required for its efficient secretion, prevents it from binding to ubiquitous cell surface receptors, and maintains its availability in a large extracellular reservoir that is readily accessed by activation. This latent TGF-beta complex (LTGF-beta) is secreted by all cells and is abundant both in circulating forms and bound to the extracellular matrix. Activation describes the collective events leading to the release of TGF-beta. Despite the importance of TGF-beta regulation of growth and differentiation in physiological and malignant tissue processes, remarkably little is known about the mechanisms of activation in situ. Recent studies of irradiated mammary gland reveal certain features of TGF-beta 1 activation that may shed light on its regulation and potential roles in the normal and neoplastic mammary gland

F. Beaufort Reduction of radiation side-effects by hydrolytic enzymes Therapeutikon, 4 (10), 1990, 577-580

fifty-seven patients who underwent radiatio for abdominal cancer were taken into a randomized prospective clinical trial. Twenty-five of these patients received concomitantly to radiatio a preparation of hydrolytic enzymes and thymus. Thirty-seven patients without enzyme therapy served as control group.

In spite of randomization the two groups showed differences: the mean duration of hospitalization was 5.7 weeks in the control group and 6.6 weeks in the enzyme group, respectively. The patients in the control group got a cumulative radiatio dose of on average 46.7 Gy, in the enzyme group of 53.4 Gy. Nevertheless, the side effects due to radiatio – mainly gastrointestinal and genito-urinary complaints were comparable in both groups as for frequency and severity. The duration of the side effects, however, showed a statistically significant advantage in favour of the enzyme group: on average, the side effects lasted 24.6 days in the control group and only 13.8 days in the enzyme group. Thus, the duration of the side effects was shortened by the enzyme therapy to an extent of 43.9%. Relevant laboratory parameters showed no or only slight changes during therapy. Double blind trials have just been started to verify these results.

Dale-PS; Tamhankar-CP; George-D; Daftary-GV Co-medication with hydrolytic enzymes in radiation therapy of uterine cervix: Evidence of the reduction of acute side effects. Cancer-Chemotherapy-and-Pharmacology,-Supplement. 2001; 47(7): S29-S34

AB: Purpose: The use of additional therapy with an oral enzyme preparation containing trypsin, chymotrypsin and papain has been suggested for the reduction of toxicity due to radiation therapy. This study was conducted to rest the efficacy and tolerability of this enzyme combination in preventing or reducing the acute side effects of radiation therapy in patients with locally advanced cervical cancer. Methods: A prospective, randomised, open, clinical trial was carried out on 120 patients (aged 24-85 years) with locally advanced, biopsy-proven carcinomas of the uterine cervix (stages IIa, IIb or IIIb). Patients received 50 Gy of external radiation therapy over a period of 5 weeks, followed by intra-cavitary brachytherapy (20-30 Gy). Patients assigned to the test group (60 patients) received additional treatment with enzymes. Patients were evaluated at weekly intervals for acute radiation therapy-related side effects, according to the RTOG/EORTC grading criteria, and then alter the end of radiation therapy for another 8 weeks. Occurrence of adverse events, if any, was also recorded. Results: The study revealed that the maximum extent of acute radiation side effects was reduced in the enzyme group: skin reactions (mean: 0.97 vs 1.68 in the control group, P < 0.001), vaginal mucosal reactions (0.55 vs 0.85, P = 0.10), genitourinary symptoms (0.93 vs 1.38, P < 0.001) and gastrointestinal reactions (1.12 vs 1.30, P = 0.12). The sum-scores during treatment, expressed as area under the curve, were significantly less in the enzyme treated patients. In the follow-up visits all observed side effects of radiation therapy were of lower intensity in the enzyme group than in the control group. Conclusions: In patients with locally advanced cancer of the uterine cervix, oral enzyme therapy was found to be effective in significantly reducing radiation therapy-related side effects such as genitourinary symptoms, subcutaneous changes and reactions of the vaginal mucosa.

A. Derveniece, I. Hartmane, I. Mikazhans, I. Chema. Local Treatment Of Skin Injuries Caused By Radiation Therapy Of Oncological Patients. Enzīmterapija (Enzymtherapie) in Lettische Sprache Nr. 2, 2000, 10-13.

Poorly healing burned wounds and atrophy of skin is not rare outcomes of radiation therapy.

Investigation of clinical efficacy of different means for topical treatment such as ointments of WOBE-MUGOS, Wobenzym N, Diaethonum, Iruxol, and also Panthenol-Spray, Fucidine crème and Solcoseryl gel were performed on 39 patients treated with radiation therapy in Oncological Center, Riga, Latvia. All patients besides of radiation therapy received one from mentioned means. Total doses of radiation for each patients was between 50-60 Gy, given as daily doses of 1,8 Gy. Efficacy of each mean was estimated measuring time of radio dermatitis, expressiveness of local edema.

After the treatment, during time of radiation therapy and 6 months observations period we obtained satisfactory efficacy in case of treatment with all testified means. We observed faster healing of erosive defects in skin using combination of Solcoseryl gel and Iruxol ointment. Also antibacterial and anti-oedematous effects of Fucidin H crème were obtained. In patients used ointment of WOBE-MUGOS® E we obtained less expressed signs of skin atrophy, typical for post-radiation lesions. In accordance to our point of view, ointment of WOBE-MUGOS® E is acceptable for prevention and treatment of skin damage in oncological patients due to adequate efficacy and price.

Gujral M.S. Patnaik P.M. Kaul R., Daftary G.V., Parikh H.K., Tamhankar C.P., Schiess W. Oral enzymes preventing side effects of radiation therapy in patients with head and neck cancers The European Journal of Cancer 1999; 35(4): No. 634, 168.

Based on in vitro data and on clinical evidence of a protective action against acute side effects of radiotherapy, a prospective randomised study was undertaken to determine the safety and efficacy of an oral enzyme combination in patients with head and neck cancer receiving conventional fractionated radiotherapy (Wobe-Mugos® E, MUCOS Pharma, Geretsried, Germany) (OE). Two study centres included 100 patients with locally advanced head and neck cancer into this open study. Radiation was delivered with telecobalt machines using standard daily radiation dose of 150-200cGy in 30-35 fractions over a period of 6 weeks. Two lateral parallel opposing fields were used with the portal area generally being 4×6 inches. Patients were randomly allocated to two groups: Patients in the test group were given OE orally three times daily starting 3 days prior to radiotherapy and continuing up to 5 days after completing radiotherapy. Patients in the control arm were not given any drug. The control group and the test group were comparable with respect to presenting features. In the test group the maximum severity and duration of mucositis, skin reaction, and dysphagia were significantly less as compared to the control group. The duration of these side effects as well as the sum scores of toxicity was also significantly less in the OE group. In summary the use of OE with conventional fractionated radiotherapy was feasible without significant safety problems. There was a clinically relevant protection against acute side effects of radiotherapy in the OE group. Not only was the severity of acute side effects less, but the duration was shorter and the time to onset was also delayed.

Heinz, R. Wobe-Mugos als adjuvante Therapie bei Patienten unter Chemo- oder Strahlentherapie. Arzt & Praxis, 757: 828-834, 1996

Wobe-Mugos ist in Österreich zur unterstützenden Therapie bei malignen Tumoren bzw. als Zusatzbehandlung während und nach einer Strahlen- oder Chemotherapie zugelassen. Im Rahmen einer Anwendungsbeobachtung an 262 Patienten mit Karzinomen bescheinigten die Ärzte der adjuvanten Therapie mit Wobe-Mugos bei 77 % der Patienten eine sehr gute oder gute Wirksamkeit. Nebenwirkungen traten nur selten auf und betrafen überwiegend den gastrointestinalen Bereich.

Kan ID, Zverev MP, Dvorkina SI. [Prevention and treatment of early radiation reactions of the urinary bladder in patients with cancer of the cervix and corpus uteri]. Vopr Onkol 1988;34(6):713-7

The report discusses early-onset radiation injuries in the urinary bladder of more than 1000 patients with cancer of the cervix and corpus uteri. Clinical symptoms of such injuries were observed in 487 patients (44.3%). In 47 (10%), the lesions were pronounced. The degree of radiation-induced cystitis was evaluated on a 6-point scale used by WHO classification (1982). Said lesions mainly occurred at stage III of tumor and predominantly in cases of cancer of the corpus uteri. Complications development was stimulated by vascular lesions, diabetes mellitus and inflammatory processes in pelvic organs. Radiation injuries were treated by standard procedures as well as with immobilised trypsin administered in a cellulose powder vehicle. This method proved the most effective. Since patients suffering early-onset radiation-induced destructive injuries are at high risk of further exacerbation at later stages, they should be followed-up closely.

R. Kaul, B. K. Mishra, P. Sutradar, V. Choudhary, and M. S. Gujral. The role of Wobe-Mugos in reducing acute sequele of radiation in head and neck cancers–a clinical phase-III randomized trial. Indian J Cancer 36 (2-4):141-148, 1999.

Oral enzymes act as a potent antiinflammatory, antiedematous agents thereby decreasing acute toxigenic effect of radiation and increasing compliance, quality of life of our patients. Fifty patients were randomized 25 allocated in enzyme and radiotherapy arm, 25 in radiotherapy alone. Pre RT and post RT biopsies were taken from both arms. In our study it was found that there was clinical, histopathological as well as statistical significant difference in both arms. The enzyme arm patients had mucostis of grade I in 76%, grade II in 12%, grade III in 8% while as 8% had grade I, 68% grade II, 24% had grade III in RT arm alone. In enzyme patients skin reactions of grade I in 72%, 20% had grade II, 8% had grade III. In control arm 12% had grade I, 76% had grade II, 8% had grade III skin reaction

F. M. Kong, M. K. Washington, R. L. Jirtle, and M. S. Anscher. Plasma transforming growth factor-beta 1 reflects disease status in patients with lung cancer after radiotherapy: a possible tumor marker. Lung Cancer 16 (1):47-59, 1996.

PURPOSE: To determine the frequency with which elevated plasma transforming growth factor-beta 1 (TGF beta 1) concentrations occur in lung cancer patients, to determine the kinetics of TGF beta 1 expression during and after radiotherapy and to correlate plasma TGF beta 1 levels with disease status after treatment. MATERIALS AND METHODS: Plasma samples were obtained before, during and after radiotherapy in 54 patients with lung cancer and 20 normal controls. Plasma TGF beta 1 levels were measured using an enzyme-linked immunosorbent assay. RESULTS: Baseline TGF beta 1 levels in lung cancer patients and normal controls were 13.0 +/- 2.5 and 4.4 +/- 0.3 ng/ml, respectively. Elevated TGF beta 1 were found in 50% (27/54) of lung cancer patients. During radiation therapy plasma TGF beta 1 levels declined, however, by the completion of treatment the mean TGF beta 1 level had not normalized in patients with lung cancer. The TGF beta 1 level at last follow-up correlated with disease status in those patients with an increased pretreatment plasma level. Three of four patients with no evidence of cancer had normal follow-up TGF beta 1 levels, compared to 2/16 patients with residual or recurrent tumor (P = 0.02). CONCLUSIONS: Elevated plasma TGF beta 1 levels occur frequently in patients with lung cancer. In those patients with an elevated plasma TGF beta 1 level at diagnosis, monitoring this level may be useful in detecting both disease persistence and recurrence after therapy.

Lukas-J; Betka-J; Klozar-J; Taudy-M; Honzikova-M., Systemic enzyme therapy in prevention of postirradiation complications Otorinolaryngologie-a-Foniatrie. 1999; 48/1 (14-17)

The authors present their initial experience with the preparation Wobenzym as a radioprotective agent. Systemic enzyme therapy was administered to 10 patients with squamous-cell carcinoma of the oropharynx after buccopharyngotomy with mandibulotomy and osteosynthesis with subsequent postoperative radiotherapy. Before the beginning of the prospective investigation Wobenzym was administered to three patients after buccopharyngotomy and mandibulotomy with osteosynthesis and postirradiation osteoradionecrosis, together with Dalacin. In patients with postirradiation necrosis also laboratory examinations of urine were made to detect pyridinium cross bonds as a marker of impaired bone metabolism. Postirradiation mucosal and osseous changes were evaluated according to the WHO scale. In none of the patients radiotherapy had to be discontinued on account of severe mucositis or dermatitis. In none of the patients of the group late postirradiation changes were detected such as osteoradionecrosis. Administration of systemic enzyme therapy as a radioprotective procedure is evaluated favourably by the authors.

T. Martin, K. Uhder, R. Kurek, S. Roeddiger, L. Schneider, H. G. Vogt, R. Heyd, and N. Zamboglou. Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic irradiation? Results of a double-blind randomized trial. Radiother Oncol 65 (1):17-22, 2002

PURPOSE: Does prophylactic treatment with proteolytic enzymes reduce acute toxicity of adjuvant pelvic radiotherapy? MATERIAL AND METHODS: Fifty-six patients with an indication for adjuvant pelvic irradiation after curative surgery were double-blind randomized. All patients took 3 x 4 capsules study medication daily during radiotherapy. Twenty-eight patients in the enzyme group (EG) received capsules containing papain, trypsin and chymotrypsin, 28 in the placebo group (PG) received placebo capsules. All patients were irradiated with 5 x 1.8 Gy weekly to 50.4 Gy using four-field-box technique after CT-based planning. Primary objective was the grade of diarrhea, nausea, vomiting, fatigue and epitheliolysis during radiotherapy. Secondary objectives were the number of supportive medications and treatment interruptions due to acute toxicity. RESULTS: None/mild diarrhea: 43% EG, 64% PG. Moderate/severe diarrhea: 57% EG, 36% PG (P = 0.11). Mean duration: 11 days in EG, 10 days in PG. None/mild nausea: 93% EG, 93% PG. Moderate/severe nausea: 7% EG, 7% PG. None/mild vomiting: 100% EG, 97% PG. None/mild fatigue: 82% EG, 93% PG. Moderate/severe fatigue: 18% EG, 7% PG (P = 0.23). None/mild epitheliolysis: 75% EG, 93% PG. Moderate/severe epitheliolysis: 25% EG, 7% PG (P = 0.16). Treatment interruption (mean days): 2.44 in EG, 1.46 in PG. Number of supportive medication: 29 in EG, 19 in PG. CONCLUSIONS: The prophylactic use of proteolytic enzymes does not reduce acute toxicities, treatment interruptions and number of supportive medication and therefore does not improve tolerance of adjuvant pelvic radiotherapy

Osterreicher-J; Skopek-J; Navratil-L; Knizek-J; Sebkova-V; Macela-A Enteral administration of proteinase mixture inhibits development of radiation pneumonitis and lung fibrosis in rats. International-Journal-of-Immunotherapy. 2000; 16(3-4): 45-51

AB: Wistar rats underwent a sublethal whole-thorax irradiation. One group of animals received a mixture of proteinases (60 mg/kg/day) by rectum every 12 h from day 1 following irradiation to the end of the experiment. Saline-treated animals were used as a control. The animals were observed for 8 and 42 weeks following irradiation. Transforming growth factor-< beta > (TGF-< beta >) 1-, 2- and 3-positive cells, alveolar septal thickness, neutrophil granulocyte number and connective tissue content in the lung tissue of the rats were measured. During the onset of the inflammatory phase, a significantly lower neutrophil number was found in the enzyme-treated rats in comparison to the saline-treated control animals. Furthermore, mixture of proteinases inhibited TGF-< beta >1 and 2 expression. During the onset of the fibrotic phase, significantly lower alveolar septal thickness, TGF-< beta >2 and 3 expression and connective tissue content were found in the group of enzyme-treated rats as compared to control rats. Based on the obtained results we suggest that specific mixtures of proteinases show both antiinflammatory and antifibrotic effects.

M. S. Pluzhnikov, M.A. Ryabova, S.A. KarpiscenkoThe effect of systemic enzyme therapy (Phlogenzym) in the treatment of radiomucositis in patients with laryngeal cancer. Folia Otorhinolaryngologica (1999): 5 (1-2), 73 – 75.

Healthy tissue surrounding oncologic lesion is regularly intervened in the course of radiotherapy, too. Three degrees of skin reaction are distinguished : 1. – erythema caused by the total doses of 30 – 35 Gy, 2. – dry dermatitis (hyperemia, edema, epidermal separation, sudoriferous and salivary gland functional impairment; skin is dry, pigmented) caused by total doses of 40 Gy, 3. – wet dermatitis, caused by the doses of 50 Gy and more. Mucosa seems to be more radio-sensitive than skin. As the basal layer gets damaged, cicatrization develops under white fibrinous deposit. The soreness makes swallowing very difficult. Xerostomia is detected as a consequence of progressive radiomucositis with impairment of salivary gland cells.

As the patients lose appetite, they mostly insist on discontinuation of radiotherapy. In order to prevent radiomucositis, a non-irritating diet is recommended as well as absence of alcohol and smoking. Postradiation disease is treated by antibiotics, analgesics, alkaline throat wash, vitamins etc.

Clinical effect of Phlogenzym on radiation-induced epitheliitis was studied at the Clinic of Otorhinolaryngology I.P.Pavlova in 15 patients suffering from laryngeal cancer. 9 patients underwent endoscopic resection of larynx, 2 patients underwent extirpation of larynx, 3 were treated by radiation only, and one patient was subject to pharyngotomy and resection of palate tonsil and tongue root. 15 patients suffering from laryngeal cancer and treated by radiation without administration of Phlogenzym served as a control group.

Xerostomia, swallowing difficulties, hyperemia, fibrinous deposits, and crusts on mucosa were recorded in the control group. In spite of the fact, that conventional palliative therapy was administered (antibiotics, NSAID, anesthetics), it was necessary to discontinue the treatment in 4 patients who refused to eat. Radiation side-effects persisted for 3 weeks up to 3 months, resulting in food intake reduction and necessary medication.

In the group of 15 patients receiving 2×3 tablets of Phlogenzym for 10 days, no case of radiomucositis of II degree was recorded, as well as the occurrence of fibrinous deposits and crusts.

The course of radiotherapy was not discontinued in any patient. Mean weight loss in the enzyme-treated patients was 5 %, while in the control group it was 10 %. Blood leukocyte count was 5 x 109 / l, while in the control group it was 3 x 109 / l. The symptoms of epitheliitis disappeared within one week after treatment. Administration of enzyme therapy alleviated the consequences of radiation-induced epitheliitis and Phlogenzym was well tolerated without any side effects.

Smolanka I.I. and Ganul V.L. Preliminary results of the combined treatment for patients with lung cancer and malignant thymomas using Wobe-Mugos. Poster at 2nd International Congress of Thorax Surgery, June 1998, Bologna, Italy, 1998.

Purpose

In order to increase effectiveness of pre- and postoperative gamma-therapy in the combined treatment of patients with locally advanced non-small cell lung cancer (NSCLC) stage IIIA and malignant thymomas we used enzyme therapy by Wobe-Mugos (Mucos Pharma).

Methods

The preoperative tumor irradiation (9 patients with NSCLC and 11-malignant thymomas) was performed daily using a “Rokus” instalation at a single dose of 5 Gy. The total focal dose reached 20 Gy. Surgery was performed after2 weeks. Irradiation was repeated on days 10-15 following surgery (30 Gy, 2,5-3,0 Gy daily). During treatment (2 month) the patients received Wobe-Mugos (6 tbl. daily).

Conclusions

Preliminary results indicate that this approach to the combined treatment is well tolerated. Wobe-Mugos in the combined treatment did not complicate the surgical procedure and the postoperative period; allowed to increase the effectiveness of gamma-therapy and decreased postradiation pneumofibrosis.

Stauder, G., Beaufort, F., and Streichhan, P. Radiation induced adverse reactions in abdominal cancer patients and their reduction by hydrolytic enzymes. Dtsch Z Onkol, 23/1: -16, 1991.

Summary

In this randomized prospective clinical trial hydrolytic enzymes were given additionally to radiation in abdominal cancer patients and compared with radiation only. The concomitant oral enzyme therapy improved the tolerance of the radiation significantly. The enzyme treated patients had less deterioration of general condition and skin symptoms and less patients discontinued radiation. It reduced the number of drugs needed for the treatment of radiation adverse effects, especially antiemetics, gastrointestinal drugs, antidepressives, tranquilizers and other psychopharmaceuticals, analgetics, spasmolytics, diuretics and aldosteron antagonists. In most cases the enzyme therapy was well or very well tolerated.

K. Vinzenz and E. Schuh. Therapie mit hydrolytischen Enzymen bei der operativen Zahnentfernung sowie bei der Strahlenmucositis. In: Systemische Enzymtherapie, edited by H. Wrba, M.-W. Kleine, K. Dittmar F. W Miehlke, and R. E. Weissenbacher, 1996, p. 57-64.

Zavadova, E., Oesterreicher, J., Desser, L., Šebková, V. and Wald, M. Reduction of transforming growth factor-beta (TGF-beta) in sera of rats with postradiation lung fibrosis after rectal administration of a mixture of proteolytic enzymes (Phlogenzym).

Radiation lung fibrosis is a final stage of postradiation changes . It has been suggested that TGF- beta may induce a chronic activation of fibroblast maturation to fibrocytes and initiate postradiation lung fibrosis development. Recently, proteolytic enzymes have been shown to reduce fibrosis development. In this study we investigated the effect of proteinase mixture Phlogenzym on the production of cytokines IL-1, IL-4, IL-10 and TGF-beta after 8 and 42 weeks following sublethal irradiation of rats. The Wistar rats underwent a sublethal whole-thorax irradiation. One group of animals received a mixture of proteinases (60 mg/kg/day) per rectum every 12 hours from day 1 following irradiation to the end of experiment. As a control, saline-treated animals were used. The animals were observed for 8 and 42 weeks following irradiation. TGF-beta1, IL1, IL 4 and IL 10 were determined by ELISA. A significant decrease in TGF- beta1 as well as IL1, IL 4 , IL 10 in sera of rats receiving proteinases could be observed in comparision to controls. The decreased sera levels correlated with decreased fibrosis development in rats treated with proteolytic enzymes. Proteolytic enzymes bind to a2Macroglobulin. Subsequently this complex binds TGF-beta and other cytokines irreversibly. The complex a2M + protease + cytokine is very quickly removed by endocytosis. Although it is necessary to perform extended studies focused on anti-fibrotic and anti-inflammatory effects of proteinases, it may be assumed that proteolytic enzymes offer a new perspective in the prophylaxis of radiation lung fibrosis.

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