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PubMedDate not supplied

Clinical pharmacology of bleomycin and cisplatin.

Bleomycin (Blenoxane) and cisplatin (Platinol) are two anticancer drugs with activity for head and neck tumors. Introduced into clinical use in the past ten years, bleomycin is used primarily in the chemotherapy of squamous cell carcinomas, lymphomas, and testicular carcinoma, while cisplatin is effective against testicular and ovarian carcinoma, head and neck cancer, bladder cancer, and neuroblastoma. Bleomycin is rapidly excreted renally (T 1/2 beta = 2-4 hr) although enzymatic inactivation also occurs in many tissues. Cisplatin is nonenzymatically converted to highly protein-bound metabolites, which then undergo renal elimination, but total body clearance occurs much more slowly than with bleomycin (T 1/2 beta = 40-50 hr). Both agents have acute and chronic toxicities; the acute toxicities are generally reversible but cause a great deal of patient discomfort, while the chronic toxicities are often irreversible and dose-limiting. For bleomycin, the acute toxicities are mucocutaneous and pyretic, while severe nausea and vomiting represent the major acute toxicities of cisplatin therapy. Cumulative dose-related pulmonary toxicity is the most serious chronic toxicity of bleomycin. The clinical, radiographic, and pathologic presentations are nonspecific, although identification of high-risk patients may be possible with serial pulmonary function tests. Cumulative nephrotoxicity occurs with cisplatin use and its incidence and severity can be reduced by maintaining adequate hydration and diuresis during and following administration of the drug.

Aged↗
PubMed1995

Mechanism of antifibrotic effect of taurine and niacin in the multidose bleomycin-hamster model of lung fibrosis: inhibition of lysyl oxidase and collagenase.

In the multiple-dose bleomycin-hamster model of pulmonary fibrosis, combined treatment with taurine and niacin blocks the increase in lung collagen deposition. We investigated the effects of taurine and niacin on lung lysyl oxidase and type I collagenase activities in this model. Hamsters were intratracheally instilled with three weekly doses of saline or bleomycin sulfate. Animals were fed either a diet containing 2.5% niacin and 2.5% taurine, or a control diet throughout the experiment. The four groups were saline-instilled with the control diet (BCD), bleomycin-instilled with the diet containing taurine and niacin (BTN), and saline-instilled with the diet containing taurine and niacin (STN). Animals were sacrificed at 1, 4, and 8 weeks after the last bleomycin instillation. Hydroxyproline per lung in the BCD group was significantly elevated by 38, 56, and 60% over the SCD group at 1, 4, and 8 weeks, respectively. Lysyl oxidase activity per lung in the BCD group was significantly elevated by 57.5 and 91.4% over the SCD controls at 1 and 4 week time periods, respectively. Type I collagenase activity per lung in the BCD group was significantly elevated by 65 and 80% over the SCD controls at 1 and 4 weeks, respectively. The combined treatment with taurine and niacin abolished the bleomycin-induced increases in the lung hydroxyproline content and lysyl oxidase and collagenase activities. It was postulated that one of the mechanisms for the antifibrotic effect of taurine and niacin may be the blockage of bleomycin-induced increases in the lung lysyl oxidase and collagenase activities.

Animals↗
PubMed2006

Evidence for TGF-beta1 and bleomycin intracellular signaling through autocrine regulation of Smad 3 binding to the proximal promoter of the Smad 7 gene.

Both Bleomycin and TGF-beta1 increase the transcription of the COL1A1 gene. Bleomycin acts through TGF-beta1. Bleomycin stimulates the COL1A1 promoter through the distal TGF-beta response element by intracellular and extracellular signaling. As demonstrated in this manuscript, Bleomycin's intracellular signaling can be explained by a decrease of Smad 3 transcription factor binding to the SBE located in the proximal promoter of the inhibitory Smad 7 gene. This would result in TGF-beta1-induced activated SMADS, which would result in more collagen. Bleomycin's extracellular signaling results from the secretion of more latent TGF-beta produced by lung fibroblasts and cleaved to active TGF-beta extracellularly. Since the TGF-beta genes are auto-induced in human embryonic IMR-90 lung fibroblasts, this study indicates an autocrine mechanism to maintain homeostasis in vivo for fibroblasts and other cell types, which produce TGF-beta1 to limit the fibrogenic response to TGF-beta1 and Bleomycin.

5' Flanking Region↗
PubMed2002

Pulsed dye laser and intralesional bleomycin for treatment of resistant viol hand warts.

BACKGROUND AND OBJECTIVE: Viral warts affect 7-10% of the population and are a major burden on time and resources of dermatology departments everywhere. Some warts prove resistant to multiple therapies, and this is particularly common in the immunosuppressed patient. Numerous treatments are available, but no one treatment has emerged as the treatment of choice. Bleomycin has been shown to be effective in treating warts, but administration can be difficult with risk of local complications. To demonstrate a new technique for easily and safely administrating bleomycin into warts, we undertook an open study to assess the practicality, efficacy, and tolerability of pulsed dye laser immediately followed by intralesional bleomycin in resistant viral hand warts. STUDY DESIGN/MATERIALS AND METHODS: Ten subjects, all with resistant viral hand warts of at least 3 years duration were recruited. Four subjects were on long-term immunosuppressant drugs. Eighteen warts treated in total. Area of the wart was anaesthetized with 1% lignocaine, then treated with a pulsed dye laser (7 mm spot, fluence 10 J/cm2). Immediately following this bleomycin (0.5 IU/ml) was injected into the base of the wart. Monthly follow-up and treatment until satisfactory clearance. RESULTS: Sixteen out of eighteen warts cleared (89%). Eight out of ten warts in the immunosuppressed subjects cleared. The remaining two warts responded partially to two treatments, but the patient was happy with the result and did not wish further treatment. All warts in the immunocompetent subjects cleared. No serious side effects were seen. CONCLUSIONS: The initial treatment of the wart with pulsed dye laser serves to "prepare" the wart for the bleomycin injection, which can then be given very easily. This ensures the drug is deposited into the base of the wart where it is most needed and minimises the risk of infiltration of normal skin or the operative environment. This method of combining pulsed dye laser and intralesional bleomycin appears to be a safe, rapid, well tolerated, and successful treatment for resistant hand warts. It has proven to be effective in warts in immunosuppressed patients and at difficult sites (e.g., subungual warts). These findings need confirmation from a larger controlled study.

Adult↗
PubMed1978

Comparison of two radioimmunoassays and a microbiologic assay for bleomycin.

Recently two radioimmunoassays have been independently developed for determination of bleomycin levels. In this study these assays are compared with each other and with a standard microbiologic assay for bleomycin. Bleomycin levels were determined in serum and urine samples obtained at varying intervals following intramuscular bleomycin injection. There were systematic differences between the assays. One radioimmunoassay indicated bleomycin levels lower than the levels indicated by the microbiologic assay with serum samples. With urine samples, both radioimmunoassays indicated bleomycin levels greater than the microbiologic assay.

Antibody Specificity↗
PubMed1984

Bleomycin pulmonary toxicity: its relationship to renal dysfunction.

Two hundred seventy-five patients who had received bleomycin were examined for evidence of pulmonary toxicity. Twenty-six patients were diagnosed as having bleomycin pulmonary toxicity and, of these, 20 (77%) were documented as having renal dysfunction without other features recognized to be associated with the development of pulmonary toxicity. In this study renal dysfunction was a most important factor in the development of bleomycin pulmonary toxicity. As bleomycin is often administered with nephrotoxic drugs, it is suggested that renal function should be checked prior to each administration of bleomycin. It is proposed that appropriate dose modifications could significantly reduce the morbidity and mortality associated with bleomycin administration.

Adult↗
PubMed1986

Effects of injury and repair of the pulmonary endothelium on lung metastasis after bleomycin.

Acute endothelial injury induced by bleomycin has been shown to enhance the localization and metastasis of circulating tumour cells. In the present study we wished to determine whether increased metastases to the lung is related to the degree of endothelial damage as indicated by morphology and protein leakage to alveoli and whether the progression to repair with pulmonary fibrosis also effects metastatic tumour growth. C57b1/6 mice were injected with a single intravenous dose of bleomycin (120 mg/kg). After 5 days, severe enothelial injury was demonstrated by morphology and by increased levels of protein in lung lavage fluid. When [131I]-iododeoxyuridine labeled syngeneic fibrosarcoma cells were injected intravenously at this time, a 9-fold increase in their localization was detected 24 h later in bleomycin-treated lungs compared with saline controls. By electron microscopy tumour cells were observed at sites of denuded vascular basement membrane. There was also a significant increase in the number of gross metastases which developed subsequently and in the percentage of lung occupied by tumour in the bleomycin group. Animals examined 10 days after bleomycin showed less endothelial damage and a smaller increase in tumour cell localization and metastases. At 21 days, when endothelial structure and alveolar protein levels had returned to normal, and at 6 weeks, when there was focal fibrosis, no increase in tumour cell localization or metastases was found. It is concluded that damage to the pulmonary endothelium is a key factor in enhancing the trapping of circulating tumour cells and increasing metastatic tumour growth after bleomycin.

Animals↗
PubMed2000

Expression of transforming growth factor-beta type I and type II receptors is altered in rat lungs undergoing bleomycin-induced pulmonary fibrosis.

Transforming growth factor-beta (TGF-beta) is a family of autocrine/paracrine/endocrine cytokines involved in controlling cell growth and extracellular matrix metabolism. TGF-beta exerts its biological effects via binding to type I (TbetaRI) and type II (TbetaRII) receptors. To gain insight into the possible role of TGF-beta receptors in the pathogenesis of pulmonary fibrosis, we investigated the expression of TGF-beta receptors and their ligands in a bleomycin-induced model of pulmonary fibrosis. We found that the expression of both TbetaRI and TbetaRII was altered in rat lungs during pulmonary fibrosis induced by bleomycin. The increase in TbetaRI mRNA level was evident after 3 days of bleomycin administration, and TbetaRI mRNA continually increased for over 12 days after bleomycin instillation, whereas TbetaRII mRNA declined at day 3 post bleomycin instillation and then increased during the reparative phase of lung injury (days 8 and 12). The immunoreactivity for both TbetaRI and TbetaRII was detected in the cells of the interstitium, the epithelium, and the blood vessels of normal rat lungs. In bleomycin-induced pulmonary fibrosis, an extensive immunostaining for TbetaRI and TbetaRII was present in the cells at the sites of injury and active fibrosis. These results demonstrate that the expression of TGF-beta type I and type II receptors was altered during pulmonary fibrosis, suggesting that the TGF-beta signal transduction pathway may be involved in the pathogenesis of lung fibrosis.

Activin Receptors, Type I↗
PubMed1994

Single base-pair deletions induced by bleomycin at potential double-strand cleavage sites in the aprt gene of stationary phase Chinese hamster ovary D422 cells.

One possible mechanism for the generation of deletion mutations is inaccurate repair of DNA double-strand breaks. In an attempt to detect such aberrant repair events in intact cells, confluent stationary phase cultures of chinese hamster ovary D422 cells, which are hemizygous for aprt, were treated for two days with low concentrations of bleomycin, and aprt mutant clones were selected and analyzed by polymerase chain reaction and DNA sequencing. Bleomycin was quite mutagenic in stationary phase cells, increasing the mutant frequency by five to 40-fold at 5 to 50% survival. While spontaneous mutations generated under these conditions were predominantly base substitutions, the majority of the bleomycin-induced mutations were very small deletions, with lesser numbers of large deletions/rearrangements and base substitutions. Although the small deletions tended to be clustered in several short segments of the gene, nucleosome positioning studies indicated that there was no consistent phasing of nucleosomes in aprt, suggesting that the clustering was due to sequence specificity rather than chromatin structure. About half of the bleomycin-induced mutations were single-base-pair (-1) deletions, and the majority of these involved deletion of one C in a G-Cn sequence (n > or = 2). At such sites, bleomycin is known to induce double-strand breaks by fragmentation of deoxyribose moieties at the same sequence position in both strands, resulting in a blunt-ended double-strand break with 5'-phosphate and 3'-phosphoglycolate termini. Thus, this sequence specificity is consistent with a model in which bleomycin-induced -1 deletions are generated by a double-strand break rejoining process involving removal of phosphoglycolate moieties from both 3' ends, followed by blunt-end ligation. The results support the view that repair of free radical-mediated double-strand breaks in mammalian cells in G1/G0 phase can be effected by such simple end-joining mechanisms, without the need for homologous recombination.

Adenine Phosphoribosyltransferase↗
PubMed1983

Kinetics of 57Co-bleomycin in sheep after intra-arterial injection in the head and neck region.

Intra-arterial (i.a.) chemotherapy for the treatment of head and neck tumors is performed on the basis of clinical reports. The hypothetical aim of i.a. chemotherapy is to achieve higher drug concentrations in the tumor than are achieved by systemic intravenous (i.v.) administration. Therefore, it is postulated that i.a. chemotherapy leads to an increased therapeutic effect at the tumor site and to a decrease in systemic drug toxicity. The lack of adequate animal experiments and the absence of prospective randomized clinical trials comparing i.a. with i.v. chemotherapy led to the present kinetic study, concerned with various modes of administration of bleomycin with the aim of achieving high cytotoxic concentrations at the required site. Radioactive bleomycin (57Co-bleomycin) was injected locally (buccal plane, group I), intra-arterially (transverse facial artery, group II; superficial temporal artery, group III; external carotid artery, group IV), and intravenously (saphenous vein, group V) in five sheep per group. Between 1 and 360 min after injection of radioactive bleomycin the urine and the systemic blood activities were determined, and the activities in the hypothetical tumor area (buccal plane) were measured continuously. The animals were killed 360 min after injection and the activities in the hypothetical tumor area, in the lymph nodes draining this area (submandibular, parotic, lateral pharyngeal) and in different tissues and organs were determined. For all groups, 70%-80% of the injected bleomycin was eliminated by the kidneys, without any significant differences among the five groups tested. The systemic blood activities measured at 5-min intervals exhibited no differences for the groups injected i.a. (II-IV) and i.v. (V). Only animals which received local injections (group I) showed lower activities for 60 min after injection as compared with the other four groups. The activities of radioactively labeled bleomycin in the hypothetical tumor area during the entire experiment (360 min) were again similar for the groups injected i.a. (II-IV) and those injected i.v. (V). However, only animals injected locally (group I) showed significantly increased activities. After the death of the animals there was again no significant difference between i.a. and i.v. administration. Only local injection led to significantly increased tissue activities. Similar results also obtained for the lymph nodes draining the hypothetical tumor area.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1983

Bleomycin and brain tumors. A review.

A logical inference from the recent reports indicating that malignant brain tumors are composed of a heterogeneous cell population is that combination chemotherapy will be required for effective brain tumor control. For several years we have been investigating the use of Bleomycin as an agent to be used in conjunction with radiation therapy and a nitrosourea compound. Since systemically administered Bleomycin does not cross the blood-brain-barrier and has significant toxicity when used parenterally in high doses, we have studied the use of smaller doses of Bleomycin injected directly into the brain tumor cavity. Such an intracerebral dose was more effective in prolonging survival of rats burdened with experimental 9L gliosarcomas than an intravenous dose that is 25 times as great. The combination of intracerebrally administered Bleomycin and radiation therapy was more effective than either modality alone. Furthermore, the combination of Bleomycin delivered intracerebrally and BCNU given systemically was more effective than either agent used alone. Finally, in a Phase I clinical of Bleomycin given via an Ommaya reservoir to eight patients with recurrent malignant brain tumors, we have demonstrated that individual doses of up to 7.5 units and cumulative doses of up to 255 units can be administered without significant toxicity.

Adult↗
PubMed1990

Assessment of pulmonary and hematologic toxicities of liblomycin, a novel bleomycin analog.

The antitumor efficacy as well as hematologic and pulmonary toxicity of Liblomycin, a new lipophilic analog of bleomycin, was evaluated in BDF1 mice. In comparison to bleomycin which was without any antitumor efficacy against P388 leukemia, a dose of 10 mg/kg Liblomycin administered on a daily schedule for 10 consecutive days resulted in a significant increase in animal survival (% T/C of 190). This therapeutic dose and schedule of drug administration did not produce any evidence of pulmonary histopathologic injury; at a similar dose and schedule bleomycin resulted in greater than 40% consolidation of alveolar lung space. Mouse lung collagen synthesis measured as rate of [3H]hydroxyproline formation was increased almost 4-fold by bleomycin 7 days following a single maximally tolerated i.v. injection (133 mg/kg); in contrast, Liblomycin (60 mg/kg) did not significantly alter the rate of lung collagen synthesis compared to saline injected control animals. Lung function was assessed by whole body plethysmography. Bleomycin produced an increase in breathing rates above control values by day 15 following administration of drug at 10 mg/kg (d1-10). Mice treated with Liblomycin did not exhibit an increased rate of breathing. Liblomycin, in contrast to bleomycin, produced mild and transient leukopenia and thrombocytopenia suggesting that this toxicity will be a limiting one in future clinical trials. The only other toxicity noted in this study was the appearance after repeated intraperitoneal administration of Liblomycin of a hepatic collagenous fibrous capsule. The capsule formation resulted in an abnormal and grossly lobulated liver which was believed to have affected animal survival. Intravenous administration of Liblomycin, however, was not associated with any detectable hepatic injury.

Animals↗
PubMed1994

The Tn5 bleomycin resistance gene confers improved survival and growth advantage on Escherichia coli.

The bleomycin resistance gene (ble) of transposon Tn5 is known to decrease the death rate of Escherichia coli during stationary phase. Bleomycin is a DNA-damaging agent and bleomycin resistance is produced by improved DNA repair which also requires the host genes aidC and polA coding, respectively, for an alkylation-inducible gene product and DNA polymerase I. In the absence of the drug, this DNA repair system is believed to cause the slower death rate of bleomycin-resistant bacteria. In this study, the effect of ble and aidC genes on the viability of bacteria and their growth rate in chemostat competitions was studied. The results indicate, that bleomycin-resistant bacteria display greater fitness under these conditions. Another beneficial effect of transposon Tn5 had been previously attributed to the insertion sequence IS 50 R. We were not able to reproduce this result with IS 50 R, however, the complete transposon was beneficial under similar conditions. Moreover, we showed the Tn5 fitness effect to be aidC-dependent. The ble gene was discovered after the fitness effect of IS 50 R had been established; it has not previously been considered to mediate the beneficial effect of Tn5. This possibility is discussed based on the molecular mechanism of bleomycin resistance.

Bleomycin↗
PubMed1982

Structure-activity relationships involved in the site-specific fragmentation of linear duplex DNAs by talisomycin and bleomycin analogs.

The fragmentation of Hind III- and Pst I-digested PM2 DNA and of Hind III-digested pBR322 DNA by bleomycin A2 and B2 and talisomycins A, B, S2b, and S10b was investigated. As observed by electrophoresis on agarose gels, the ethidium bromide staining band patterns produced following incubation of the various restriction endonuclease-digested DNAs with the compounds were different for the bleomycin analogs and for the talisomycin analogs. Quantitation of the degree of fragmentation of various segments of linear PM2 DNA by either bleomycin A2 or talisomycin A indicated that certain segments of the PM2 genome serve as better substrates than other segments for double-strand fragmentation by either of the two antitumor antibiotics. These results show that in this system bleomycin and talisomycin analog treatment of linear PM2 or pBR322 DNA resulted in breakage of DNA, producing different-length DNA fragments, and demonstrate the importance of the two amino acids and the 4-amino-4,6-dideoxy-L-talose sugar, which are located near the bithiazole in talisomycin but absent in the bleomycin structure in conferring a different site-specificity for DNA fragmentation to talisomycin than to bleomycin.

Antibiotics, Antineoplastic↗
PubMed1982

Minor role of lipid peroxidation in acute bleomycin toxicity in rats.

Bleomycin was injected i.p. in rats, and the amount of expired ethane which indicates lipid peroxidation was followed up for 78 h. Compared to controls neither 1 x 30 mg/kg and 2 x 30 mg/kg nor 1 x 70 mg/kg bleomycin led to increased ethane expiration, although body weight loss indicated toxicity. That pulmonary toxicity had been developed due to the acute bleomycin treatment could be demonstrated by histological examinations of lungs of the animals of the highest dosage group. The combined treatment of rats with bleomycin and ferrous ions neither resulted in an increase of ethane expired compared to that of the ferrous ion-treated animals. Rather a decrease was observed. Our results indicate that acute bleomycin toxicity is not associated with increased lipid peroxidation. Furthermore, our data suggest that the bleomycin-ferrous-complex does not initiate lipid peroxidation in vivo.

Animals↗
PubMed1980

[Animal experiments for intra-arterial chemotherapy with bleomycin (author's transl)].

Intra-arterial chemotherapy for treatment of head and neck carcinomas is performed on the basis of clinical reports, which postulate higher effective concentrations at the tumor for this therapeutic method than after systemic administration. This assumption, which has so far not yet been confirmed experimentally, has led to the present study. The study is concerned with different modes of application of bleomycin with the aim to achieve high cytostatic concentrations at the site of action required. In sheep the tissue concentration of 57Co-bleomycin was determined in a hypothetical tumor area, the planum buccale, and in the lymph nodes draining this area, after submucous administration (hypothetical tumor area), intra-arterial administration (A. transversa faciei, A. temporalis superficialis, A. carotis externa) and i.v. administration (V. saphena). Only submucous injection led to significantly increased 57Co-bleomycin activities in the hypothetical tumor area and in the corresponding primary draining lymph nodes. The intra-arterial administration into the A. temporalis superficialis and A. carotis externa did not show any differences compared to the i.v. injection of 57Co-bleomycin. Compared to i.v. administration, injection into the isolated A. transversa faciei led to a slightly increased concentration of radioactively labeled bleomycin, restricted to the hypothetical tumor area. The findings made by animals experiments print out that the clinical application of intra-arterial is not justified and favor intratumoral treatment of head and neck carcinomas with bleomycin.

Animals↗
PubMed1993

Pulmonary toxicity in patients with non-Hodgkin's lymphoma treated with bleomycin-containing combination chemotherapy.

Subclinical and clinical bleomycin-induced pulmonary toxicity (BIP) were investigated retrospectively in 109 patients with non-Hodgkin's lymphoma treated by combination chemotherapy containing bleomycin. A decrease in carbon monoxide diffusing capacity (DLCO) was found in 12.8% of patients. The cumulative risk of abnormal DLCO increased with the increasing total cumulative dose of bleomycin. No significant difference in the rate of BIP was observed between patients receiving bleomycin/Adriamycin/cyclophosphamide/vincristine/prednisone (BACOP; bleomycin given at 10 mg/m2 for 4 weeks) and bleomycin/Adriamycin/cyclophosphamide/vincristine/dexamethasone/methotre xate/ folinic acid (m-BACOD; bleomycin given at 4 mg/m2 for 3 weeks, methotrexate given at 200 mg/m2. Monitoring for subclinical BIP should be considered in patients with non-Hodgkin's lymphoma even if only a low dose of bleomycin was given in the presence of other chemotherapeutic agents.

Adolescent↗
PubMed1995

Restoration of interleukin-2 production in tumor-bearing rats through reducing tumor-derived transforming growth factor beta by treatment with bleomycin.

We studied mechanisms of immunosuppression caused by tumor-derived transforming growth factor-beta (TGF beta) and restoration of the immune response by treatment with bleomycin in rats bearing KDH-8 hepatoma. Interleukin-2 (IL-2) production from splenocytes of KDH-8-tumor-bearing rats progressively decreased as the KDH-8 tumor grew. IL-2 production from concanavalin-A-stimulated normal rat splenocytes was significantly inhibited by in vitro cultured KDH-8-tumor-cell-conditioned medium; this inhibition could be blocked by neutralizing the conditioned medium with anti-TGF beta antibody. TGF beta activities were found in KDH-8-tumor-tissue-conditioned medium without acid treatment and were found in tumor-cell-conditioned medium after acid treatment; TGF beta mRNA and TGF beta protein were found in cultured KDH-8 tumor cells. These results suggested that the KDH-8-tumor-derived TGF beta might be involved in the inhibition of IL-2 production from splenocytes. To determine whether bleomycin chemotherapy could reduce tumor-derived TGF beta and restore the immune responses, we treated KDH-8 tumor-bearing rats with bleomycin (5 mg/kg, one shot) at an appropriate time (before the occurrence of immunosuppression) resulting in a significant reduction of TGF beta activity in KDH-8 tumor tissues and restoration of IL-2 production from splenocytes of tumor-bearing rats; KDH-8 tumor growth ultimately regressed. In vitro experiments also showed that TGF beta activity, mRNA expression, and protein synthesis in KDH-8 tumor cells were reduced by bleomycin treatment, and that bleomycin-treated-KDH-8-tumor-cell-conditioned medium did not inhibit IL-2 production from normal rat splenocytes. These results suggest that bleomycin treatment restored IL-2 production in tumor-bearing rats through reducing the tumor-derived TGF beta.

Animals↗