peplomycin and Pulmonary-Fibrosis

To analyse the mechanism by which a bleomycin derivative, peplomycin (PLM) induces pulmonary fibrosis, we investigated differentiation of rat pulmonary fibroblasts to myofibroblasts (MF). In intraperitoneally PLM (5 mg/kg/day)-injected rats, the peripheries of lungs adjacent to the pleura revealed advanced fibrosis with a small number of alpha-smooth muscle actin (alpha-SMA)-positive MF, which ultrastructurally possessed abundant microfilaments and cellular organelles. In the fibrotic tissue, the expression of alpha-SMA-mRNA was detected by in situ reverse transcription-polymerase (RT-PCR). The message was strong just after a 2-week administration of PLM then decreased thereafter, although fibrosis advanced. When pulmonary fibroblasts were separated from saline-injected rats (N-Fib) and cultivated for 7 days in the presence of 5 mg/mL PLM, alpha-SMA protein was weakly expressed, while the majority of pulmonary fibroblasts separated from PLM-injected rats (P-Fib) became positive for alpha-SMA in 7-day cultivation and the expression of alpha-SMA in P-Fib was strongly increased by cultivation in the presence of PLM and transforming growth factor-beta (TGF-beta), but not basic fibroblast growth factor (bFGF) or platelet-derived growth factor (PDGF), although the cell proliferation was most strongly enhanced by bFGF and only slightly by PLM and TGF-beta. The alpha-SMA-positive cells expressed vimentin, but only weakly expressed desmin. Additionally, P-Fib generated larger amounts of TGF-beta and bFGF than were generated by N-Fib. These results indicate that PLM induces pulmonary fibrosis by differentiating fibroblasts to alpha-SMA-positive MF, and that bFGF and TGF-beta play each critical role in the different phases of PLM-induced pulmonary fibrosis by inducing fibroblast proliferation and transformation, respectively.

Topics: Actins; Animals; Antibiotics, Antineoplastic; Blotting, Northern; Blotting, Western; Cell Culture Techniques; Cell Differentiation; Cell Division; Fibroblast Growth Factor 2; Fibroblasts; Gene Expression Regulation; Male; Peplomycin; Pulmonary Fibrosis; Rats; Rats, Inbred F344; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Transforming Growth Factor beta

The pathogenesis of pulmonary fibrosis (PF) induced by bleomycin and its derivative, peplomycin (PEP), is insufficiently understood. To prevent PF and to administer PEP safely, we examined the influence of PEP on pulmonary function in 135 patients who underwent concomitant chemo (PEP + 5-FU)-radio (60Co) therapy and pulmonary function tests. In the inductive therapy, 5 mg of PEP was intramuscularly injected three times a week and a total of 41.6 +/- 14.3 mg was administered. Of the patients, 98 received oral azelastine hydrochloride (AZH, 4 mg/day) during the inductive therapy with the aim of prophylaxis of PF. The oxygen partial pressure in arterial blood (PaO2) only slightly decreased from 84.2 +/- 12.1 mmHg before treatment to 82.8 +/- 12.5 mmHg after treatment, while, carbon oxide diffusion (%DLco) decreased after treatment in most patients (p < 0.001, by paired t test) with mean values before treatment of 106.3 +/- 24.5% and after treatment 99.5 +/- 24.9%. The decrease of %DLco was associated with the dose of PEP until about 40 mg but further decreases of %DLco were not prominent. In the patients who underwent oral AZH, the decrease of %DLco weaker than that in patients without AZH: the decrease rates of %DLco in the former and latter were 4.3 +/- 9.4% and 14.1 +/- 15.9%, respectively. From the chest X-ray examination, mild PF was suspected in three patients but no advancement of PF or clinical symptoms were observed. From these results, it was concluded first that %DLco is more useful than PaO2 as the predisposing risk factor for PF, second that the decrease of %DLco depends on the dose of PEP until about 40 mg, third that AZH is expected to inhibit PEP-induced PF, and fourth that a small dose (20-40 mg) of PEP can be administered without inducing PF if care is exercised as to the patient's age, general condition and the value of %DLco in the use of PEP.

Topics: Aged; Antibiotics, Antineoplastic; Humans; Lung; Middle Aged; Mouth Neoplasms; Oxygen; Partial Pressure; Peplomycin; Pulmonary Fibrosis; Respiratory Function Tests

Inhibition of peplomycin (PLM)-induced pulmonary fibrosis by azelastine hydrochloride (Azeptin) was examined using ICR mice, and the effects of both drugs on signal transduction were investigated. Microscopically, Azeptin (a total of 56 mg/kg for 28 days) suppressed pulmonary fibrosis in mice which received an i.p. injection of a total of 60 or 75 mg/kg PLM. In parallel with the microscopic findings, smaller amounts of collagen were synthesized in the lungs of Azeptin-injected mice. PLM enhanced the expression of interleukin-1 beta- and transforming growth factor-beta-mRNA in lungs. In contrast, Azeptin suppressed the expression. Compatible with these in vivo results, Azeptin and PLM contradictively regulated protein tyrosine phosphorylation and c-myc mRNA expression in human gingival and mouse pulmonary fibroblasts. In addition, NF-kappa B was activated by fibroblast treatment with 5 micrograms/ml PLM for 1 h, but intranuclear NF-kappa B was decreased by cell treatment with 10(-5) M Azeptin. From these results, it is concluded that Azeptin inhibits PLM-induced pulmonary fibrosis by antagonizing the up-regulation of signal transduction.

Topics: Animals; Cytokines; Humans; Male; Mice; Mice, Inbred ICR; NF-kappa B; Peplomycin; Phosphorylation; Phthalazines; Proto-Oncogene Proteins c-myc; Pulmonary Fibrosis; RNA, Messenger; Signal Transduction; Tyrosine; Up-Regulation

The influence of peplomycin (PLM) on the respiratory burst of peripheral blood polymorphonuclear leukocytes (PMN) was investigated. Short-term (5 min) treatment of human PMN with 0.1mu g/ml to 100mu g/ml of PLM increased phorbol myristate acetate (PMA)- and formyl-methionyl-leucyl-phenylalanine (FMLP)-induced luminol-dependent chemiluminescence. PMN, as well as alveolar macrophages from rabbits treated with 0.5 to 1.0 mg/kg of peplomycin per day for 5 days, generated more superoxide (O2-) than the cells from untreated rabbits. In both PLM-treated and untreated PMN, chemiluminescence induced by FMLP and PMA was decreased to less than 50% of the control by staurosporine, superoxide dismutase (SOD) and catalase. However, the peak intensity in PLM-untreated PMN was decreased to about 30% of the control by genistein, while this agent induced a slight decrease in peak intensity in the PLM-treated PMN. Inositol triphosphate and diacyl glycerol levels were not clearly increased by PLM, but an increase of intracellular Ca++ and a shift of protein kinase C (PKC) to the membrane occurred in PMN within 1 min after PLM treatment. Western blotting revealed that the tyrosine phosphorylation of a 115 kDa protein was upregulated by 5 to 50mu g/ml of PLM. While, PLM suppressed SOD activity in alveolar macrophages and PMN. These results seem to indicate that PLM increases the respiratory burst of PMN and macrophages both by way of direct PKC activation and by the upregulation of protein tyrosine phosphorylation. This increased reactive oxygen generation, together with the suppression of SOD activity seems to be tissue-impairing.

Topics: Humans; Macrophages, Alveolar; Neutrophils; Peplomycin; Pulmonary Fibrosis; Respiratory Burst; Up-Regulation

A comparative clinical study examined the preventive effect of ticlopidine hydrochloride (hereinafter referred to as ticlopidine, anti-platelet drug) on Peplomycin sulfate (hereinafter referred to as Peplomycin) pulmonary fibrosis. In clinical evaluation, pulmonary function (PaO2, DLco) and biological fibrosis markers (angiotensin I converting enzyme, type III procollagen peptide, phospholipid) were measured. PaO2 and DLco using ticlopidine showed improvement, but statistical significance was not observed. Changes in biological fibrosis markers due to Peplomycin administration were observed in accordance with earlier experiments. Importantly however, the variance of type III procollagen peptide in the ticlopidine group was significantly suppressed (p less than 0.10). As a result, ticlopidine has the potential to prevent Peplomycin pulmonary side effects during clinical use.

Topics: Bleomycin; Humans; Infusion Pumps; Peplomycin; Pulmonary Fibrosis; Ticlopidine; Urologic Neoplasms

A 77-year-old man with recurrent lung cancer was administered peplomycin (PEP) 15 mg 1A only one time, from a link in the chain of chemotherapy. But just after it was occurred dyspnea, and heard crepitus by auscultation. And it was recognized of ground glass appearance and air-bronchogram in the entire lung field by chest X-ray photograph, so made a diagnosis of acute diffuse interstitial pneumonia by clinical. He died two days after in spite of emergency treatment, that is high dose steroid, O2 flow etc. We discussed the acute pulmonary side effect of peplomycin which is one of the carcinostatic antibiotic, according to this clinical progress.

Topics: Aged; Bleomycin; Carcinoma, Squamous Cell; Humans; Infusions, Intravenous; Lung Neoplasms; Male; Neoplasm Recurrence, Local; Peplomycin; Pulmonary Fibrosis

To determine the effect of continuous subcutaneous infusion of peplomycin on both antitumor activity and pulmonary toxicity, thirty-two patients with previously untreated oral squamous carcinoma were given peplomycin via osmotic microinfusion pump (SP-5, Nipro Co., Ltd.) at a daily dose of 5.0 mg subcutaneously. The mean dosage of peplomycin given was 79.8 mg. An overall response rate of 62.5% was achieved, with 21.9% complete response, and 40.6% partial response. The maximum reduction of tumor volume for responder could be generally observed when peplomycin was given at about 60 mg continuously. The most frequently encountered toxicity was a mucocutaneous reaction, manifested by stomatitis (34.4%) and skin eruption (18.8%), but they were mild and tolerable. A local skin reaction also occurred at the site of drug injection, and an ulcer formation developed in 12.5% of patients. Monitoring of pulmonary function by means of PaO2 revealed that 32.0% of patients had a decrease over 10% after peplomycin administration. However, interstitial pneumonitis eventually occurred in only one patient (3.1%). In conclusion, the regimen of continuous infusion of peplomycin is a useful method to administer peplomycin safely without reducing the antitumor effect compared to conventional intermittent injection.

Topics: Adult; Aged; Bleomycin; Carcinoma, Squamous Cell; Drug Eruptions; Female; Humans; Infusion Pumps; Infusions, Parenteral; Lung; Male; Middle Aged; Mouth Neoplasms; Oxygen; Partial Pressure; Peplomycin; Pulmonary Fibrosis; Remission Induction; Skin; Skin Ulcer; Stomatitis

In order to find a method to ameliorate pulmonary toxicity of peplomycin (PEP), microscopic changes of the lung following PEP administration and effect of anti-platelet aggregating agents on the toxicity was investigated in mice. When PEP was administered intravenously once a day for 7 days, microthrombi mainly composed of aggregated platelets and fibrin appeared in the capillaries of the lung in an early phase before severe pulmonary edematous lesions and fibrosis occurred. Combination therapy of anti-platelet aggregating agents such as phthalazinol, dipyridamole, ticlopidine and indomethacin suppressed these toxic changes. Especially, ticlopidine was the most effective and superior to prednisolone used clinically for amelioration of the toxicity. Microthrombi, preceding edematous lesions, were considered to be attributed to damages of endothelium by PEP, because PEP itself did not develop platelet aggregation in vitro and ex vivo. Therefore, the microthrombi are likely to produce congestion of pulmonary microcirculation leading to edematous lesions by increase of permeability, and to play significant roles in the development of pulmonary fibrosis in a late phase. Anti-platelet aggregating agents such as ticlopidine are concluded to ameliorate the lung toxicity by preventing microcirculation impairment with the microthrombus.

Topics: Animals; Bleomycin; Lung Diseases; Male; Mice; Mice, Inbred ICR; Peplomycin; Platelet Aggregation Inhibitors; Pulmonary Edema; Pulmonary Embolism; Pulmonary Fibrosis; Ticlopidine

Topics: Bleomycin; Female; Humans; Lipid Peroxides; Lung Neoplasms; Male; Peplomycin; Peptide Fragments; Peptidyl-Dipeptidase A; Phospholipids; Procollagen; Pulmonary Fibrosis; Radiotherapy; Testicular Neoplasms

Pulmonary toxicity was examined by means of Matsuda and Takahashi's procedure in peplomycin solution, and two types of a new dosage form of peplomycin (PEP-CH), which has peplomycin adsorbed on to activated carbon particles. One was PEP-CH IP, and is designed for intraperitoneal administration. The other was PEP-CH IM, for intramuscular administration. Male mice of ICR strain received a bolus injection of 50 mg kg-1 peplomycin in the form of aqueous solutions PEP-CH IP and PEP-CH IM. The survival rate was 100% after 5 weeks in both groups that were administered PEP-CH. The rate was 50% for the group given peplomycin solution intraperitoneally, and 70% for the group given peplomycin solution intramuscularly. Five weeks after administration the mice were killed, and the grade and the incidence of pulmonary fibrosis were evaluated histologically. The grade and incidence of pulmonary fibrosis were zero in the two groups given PEP-CH. The grade was 0.33 and 1.76, and the incidence was 60% and 86%, respectively, in the group given peplomycin solution intraperitoneally and in the group given peplomycin solution intramuscularly.

Topics: Adsorption; Animals; Bleomycin; Carbon; Lung; Male; Mice; Mice, Inbred ICR; Peplomycin; Pulmonary Fibrosis

Topics: Adult; Aged; Aged, 80 and over; Anesthesia; Bleomycin; Female; Humans; Intraoperative Care; Male; Middle Aged; Oxygen Inhalation Therapy; Peplomycin; Postoperative Complications; Pulmonary Fibrosis; Risk; Surgical Procedures, Operative

Topics: Aged; Bleomycin; Carcinoma, Squamous Cell; Humans; Lung Neoplasms; Male; Peplomycin; Pulmonary Fibrosis

Topics: Adult; Bleomycin; Cisplatin; Dose-Response Relationship, Drug; Drug Administration Schedule; Humans; Injections, Intramuscular; Lung; Male; Neoplasms, Germ Cell and Embryonal; Peplomycin; Pulmonary Fibrosis; Radiography; Testicular Neoplasms; Vinblastine

Pulmonary fibrosis in mice induced by peplomycin (PEP) was suppressed by administration of anti-inflammatory agents such as prednisolone and D-penicillamine during or after the administration of PEP. Pulmonary fibrosis was also suppressed by administration of cyclophosphamide, an immunosuppressive antitumor agent before, during or after the administration of PEP. The pulmonary fibrosis in athymic nude mice induced by PEP was less than that in normal mice. The low response in the nude mice was enhanced by transfer of thymocytes to the same level as that in the normal mice. This suggests that the immune system, especially thymus-dependent immunity, is involved in the pulmonary fibrosis induced by PEP.

Topics: Animals; Bleomycin; Cyclophosphamide; Mice; Mice, Nude; Penicillamine; Peplomycin; Prednisolone; Pulmonary Fibrosis; Rats; Thymus Gland

The pulmonary fibrosis caused by peplomycin (PEP) was studied in terms of oxygen toxicity using ICR mice. When 16 micrograms of PEP was administered intratracheally in mice after exposure to the air containing 75% O2 for 10 days, the pulmonary fibrosis was completely suppressed, while when mice were exposed to 75% O2 after the administration of PEP, the fibrosis was much severe than that of mice raised in atmospheric air. In 50% O2, similar oxygen effect was also observed, but it was weaker than that in 75% O2. In 90% O2, the oxygen toxicity was observed in mice without administration of PEP. When mice were exposed to 75% O2, the activities of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase, which are relevant to the detoxication of active oxygen species, were not increased in the lung, but the levels of reducing agents such as glutathione and ascorbic acid, and high molecular substances having 1O2-scavenging activity were enhanced. The results suggest that these materials have some roles to decrease the pulmonary fibrosis caused by PEP.

Topics: Animals; Antibiotics, Antineoplastic; Ascorbic Acid; Bleomycin; Catalase; Glutathione; Glutathione Peroxidase; Glutathione Reductase; Lung; Mice; Mice, Inbred ICR; Oxygen; Peplomycin; Pulmonary Fibrosis; Superoxide Dismutase

Pneumonitis-fibrosis which was induced by the treatment with antineoplastic agent(s) and/or irradiation was encountered in 37 (14.1%) of a total of 515 patients with lung cancer who had been treated in our institute during a period of seven years from 1976 through 1982. Of 251 patients who had been treated with bleomycin or pepleomycin alone or in combination with other antineoplastic agent(s) or irradiation, 46 (18.3%) had pneumonitis-fibrosis and 19 (7.6%) died therefrom. It was revealed that the patients over 50 years of age, whose PaO2 and % VC prior to the treatment with bleomycin were less than 79 mmHg and 79% respectively appeared to be predisposed to bleomycin pulmonary toxicity. Most of the pneumonitis which developed in these patients was progressive and fatal. Daily oral administration of 10 mg of prednisolone was in effective for the prevention of bleomycin-induced pneumonitis-fibrosis. A sudden decrease of PaO2 and a sharp elevation at a certain point in time during treatment were indicative of the fatal outcome of toxic pulmonary complications. Thoracic irradiation prior to, concomitant with or after bleomycin therapy enhanced the pulmonary toxicity of bleomycin. Therefore, combination therapy should be avoided. A continuous intravenous infusion may be the most effective and least toxic method to administer bleomycin.

Topics: Adenocarcinoma; Antibiotics, Antineoplastic; Bleomycin; Carcinoma, Small Cell; Carcinoma, Squamous Cell; Female; Humans; Lung Neoplasms; Male; Peplomycin; Prognosis; Pulmonary Fibrosis

Chemotherapy regimens containing pepleomycin, a derivative of bleomycin, were used for 81 patients with advanced primary lung cancer and 32 patients with metastatic pulmonary tumors. Among the patients with non-small cell carcinoma of the lung, partial responses were observed in three of 27 patients treated with pepleomycin + carbazilquinone and four of 26 patients treated with pepleomycin + mitomycin C (published in Cancer Treatment Reports, 1983). Five partial responses (primary organ: larynx, esophagus, lung, pancreas and uterus; one patient each) in 23 evaluable patients with metastatic pulmonary tumors were observed during treatment, for an overall response rate of 21.7%. In patients with primary lung cancer, no correlation between the incidence of the decrease in partial arterial oxygen tension (PaO2) during treatment and age was observed. Decrease in PaO2 during treatment was found more frequently in patients with abnormal pulmonary function before treatment than in patients with normal pulmonary function, but the mean lowest values of PaO2 in the two groups were the same. Intravenous weekly injection of pepleomycin is less likely to result in a decrease in PaO2 than two daily intramuscular injections. Definite pulmonary toxicity occurred in seven of the 113 patients (6.2%). Each of the seven received a total dose of over 60 mg and their ages were over 60 yr, although no correlation between the incidence of pulmonary fibrosis and total cumulative dose of pepleomycin was observed. Six of the seven patients died of pulmonary fibrosis in spite of prednisone treatment. Clinical, radiologic and histopathologic findings associated with pepleomycin were the same as those of bleomycin pulmonary toxicity. Further studies are needed to determine the appropriate dose schedule and route of administration of pepleomycin with regard to its benefit and toxicity.

Topics: Age Factors; Aged; Antibiotics, Antineoplastic; Bleomycin; Carbazilquinone; Drug Therapy, Combination; Humans; Lung; Lung Neoplasms; Middle Aged; Oxygen; Peplomycin; Prednisone; Pulmonary Fibrosis

Effect of peplomycin sulfate (PLM) on pulmonary fibrosis was examined. Hydroxyproline, uronic acid, proline hydroxylase (EC 1.14.11.2) and glucosamine 6-phosphate synthetase (EC 2.6.1.16) in lungs of hamsters treated with PLM were studied and compared with those of hamsters treated with bleomycin (BLM). PLM, when administered intraperitoneally, one injection daily for 10 consecutive days, at either a high- (5 mg/kg) or low- (2.8 mg/kg) dosage-level, caused no significant increase of lung hydroxyproline and uronic acid as compared with controls. BLM on the other hand effected a significant increase in lung hydroxyproline on the high-dosage level (5 mg/kg) but not on the low-dosage level (2.8 mg/kg). In contrast, when administering PLM intratracheally, the concentrations of hydroxyproline in lungs increased 20% over the control levels. A transient increase of proline hydroxylase and glucosamine 6-phosphate synthetase also occurred shortly after the instillation. These increases were also observed in the corresponding groups treated with BLM, which confirmed the previous observations by other investigators. However, the magnitude of the increase was relatively lower in those values of PLM as compared with those of BLM. These data suggested that (1) PLM, when administered with multiple dosages intraperitoneally, showed no significant effect on the elevation of lung hydroxyproline; (2) PLM, when administered with a dose intratracheally, induced pulmonary fibrosis similar to that caused by BLM. However, the hydroxyproline accumulation in lungs of PLM-treated hamsters was less than in those of the BLM-treated; (3) The fibrotic effect on the lungs caused by either PLM or BLM was probably attributed to acceleration of the syntheses of collagen and acidic glycosaminoglycans.

Topics: Animals; Anti-Bacterial Agents; Bleomycin; Carbohydrate Epimerases; Cricetinae; Glutamine-Fructose-6-Phosphate Transaminase (Isomerizing); Hydroxyproline; Kinetics; Lung; Mesocricetus; Peplomycin; Procollagen-Proline Dioxygenase; Pulmonary Fibrosis; Structure-Activity Relationship; Time Factors; Uronic Acids

Topics: Animals; Antibiotics, Antineoplastic; Bleomycin; Collagen; Cricetinae; Lung; Male; Peplomycin; Pulmonary Fibrosis