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PubMed1978

Bleomycin hypersensitivity pneumonitis.

Three patients developed radiologic and functional pulmonary changes after bleomycin therapy similar to ones previously associated with administration of this drug. However, biopsy specimens showed a pattern consistent with hypersensitivity pneumonitis rather than the interstitial pneumonia usually reported in bleomycin pulmonary toxicity. There was a patchy eosinophilic infiltrate surrounding small airways and distal air spaces, but no immune deposits were noted by ultrastructure or immunofluorescence using conventional techniques and a specific antibody against bleomycin. Two of the patients had peripheral eosinophilia of 12% and 16%. All three patients showed considerable improvement on chest roentgenogram after corticosteroid treatment. Our findings are consistant with the view that bleomycin hypersensitivity pneumonitis has a different pathogenesis than bleomycin interstitial pneumonitis. Its recognition as a separate entity seems warrnated because of the favorable response to steroid therapy.

Adolescent↗
PubMed2000

Fatal toxic effect of bleomycin on brain tissue after intracystic chemotherapy for a craniopharyngioma: case report.

OBJECTIVE AND IMPORTANCE: Craniopharyngiomas are benign neoplasms of epithelial origin that arise from the remnants of Rathke's pouch and are located in the sellar, parasellar, and third ventricular regions. Despite major advances in microsurgical techniques, total removal of these tumors is associated with a high risk of death, long-term endocrinological dependence, cognitive dysfunction, and behavioral disorders. For patients with monocystic craniopharyngiomas, encouraging postoperative survival rates and high rates of cyst regression after intracavitary administration of bleomycin have been reported. Moreover, only a few side effects have been reported for this treatment method. We report a patient with a cystic craniopharyngioma who was treated using intracavitary bleomycin administration and died as a result of the direct toxic effects of bleomycin on deep brain structures and the brainstem. CLINICAL PRESENTATION AND INTERVENTION: A 47-year-old woman with a cystic craniopharyngioma underwent stereotactic insertion of a catheter attached to a subcutaneous reservoir. Five months after the procedure, positive-contrast computed tomographic cystography was performed to confirm the absence of fluid leakage. Daily intracavitary injections of bleomycin were administered through the reservoir into the cyst, until a total dose of 56 mg had been administered in 8 days. After the treatment, the cystic cavity regressed but the patient exhibited neurological deterioration; magnetic resonance imaging scans revealed diffuse edema in the diencephalon and brainstem. The patient died 45 days after completion of the treatment. CONCLUSION: Intracavitary administration of bleomycin is not a treatment protocol without risks or side effects, even if there is no fluid leakage into the cerebrospinal fluid. Although this is known to be an effective treatment for cystic craniopharyngiomas, previous reports cannot be used to establish a standard treatment method, and more research is needed to yield a safer effective protocol.

Antimetabolites, Antineoplastic↗
PubMed2000

Bleomycin stimulates lung fibroblast and epithelial cell lines to release eosinophil chemotactic activity.

The presence of eosinophils in the lungs of patients with pulmonary fibrosis correlates with poor prognosis or resistance to therapy. Furthermore, eosinophils localize to areas undergoing active fibrosis. It was hypothesized that a human lung fibroblast (HFL-1) and a human lung epithelial cell line (BEAS-2B) might release eosinophil chemotactic activity (ECA) in response to bleomycin, a chemotherapeutic agent associated with pulmonary fibrosis. HFL-1 and BEAS-2B cells were cultured in the presence of bleomycin and their supernatant fluids evaluated for ECA by means of a Boyden chamber method. HFL-1 and BEAS-2B cells released ECA in a dose- and time-dependent manner in response to bleomycin, and partial characterization revealed that the ECA was heterogeneous. ECA release from HFL-1 and BEAS-2B cells was significantly reduced by a leukotriene B4 (LTB4) receptor antagonist and an antibody directed against granulocyte-macrophage colony-stimulating factor. HFL-1 cells released LTB4, eotaxin, and GM-CSF constitutively, and BEAS-2B cells released LTB4, eotaxin, regulated on activation, normal T-cell expressed and presumably secreted, and GM-CSF constitutively. In both cases, the release of GM-CSF was significantly increased in response to bleomycin. These data suggest that lung fibroblasts and epithelial cells may modulate eosinophil recruitment into the lung in bleomycin-induced pulmonary fibrosis.

Antibodies↗
PubMed2001

Bleomycin in the treatment of keloids and hypertrophic scars by multiple needle punctures.

BACKGROUND: The treatment of keloids and hypertrophic scars has been difficult and a recent French study showed that bleomycin has been useful in the treatment of these lesions. OBJECTIVE: To determine the effectiveness and safety of bleomycin in the treatment of hypertrophic scars and keloids when this drug is administered through multiple superficial punctures. METHODS: We applied bleomycin to keloids and hypertrophic scars in 13 patients using a multiple-puncture method on the surface of the skin. All patients were given bleomycin at a concentration of 1.5 IU/ml. Clinical response after treatment was classified according to the following scale: complete flattening (100%), highly significant flattening (>90%), or significant flattening (75-90%). RESULTS: The clinical response was very positive in all cases: complete flattening in six cases, highly significant flattening in six cases, and significant flattening in one case. Two patients presented a recurrence as a small nodule 10 and 12 months after the last infiltration. CONCLUSIONS: These clinical findings show that administration of bleomycin in keloids and hypertrophic scars shows promise and needs further investigation.

Adolescent↗
PubMed1999

[The effect of aminoguanidine, a nitric oxide synthase inhibitor, on bleomycin-induced lung injury in rats].

OBJECTIVE: To observe the dynamic change of the nitric oxide synthase (NOS) activity of the lung in bleomycin -induced pulmonary fibrosis in rats and to investigate the effect of aminoguanidine (AG), a selective inhibitor of inducible NOS on this animal model. METHODS: Sixty SD rats were divided into three groups in random: control group, untreated model group, AG-treated group. On experimental day (day 0), the rats were intratracheally instilled with bleomycin (5 mg/kg body weight) or sterile saline, and then treated with AG (50 mg x kg(-1)) x d(-1)), intraperitoneally) or saline until they were killed. On days 3, 7, 14, 28 after instillation, five rats of each group were sacrificed and the lungs were harvested for histopathological examination and determination of NOS activity, MDA and TNF. RESULTS: NOS activity in the lung homogenate was elevated quickly after bleomycin instillation and peaked on day 7, then declined. Treatment of AG remarkably ameliorated the alveolitis caused by bleomycin. The subsequently pulmonary fibrosis was also decreased, but there was no statistically significance. AG did not affect the increased level of MDA and TNF-alpha caused by intratracheally instilled bleomycin. CONCLUSIONS: Nitric oxide seems to play an important role in the development of pulmonary fibrosis, especially in the alveolitis phase.

Animals↗
PubMed2002

[Role of induction chemotherapy with bleomycin A5 in treating stage T2 tongue squamous cell carcinoma].

BACKGROUND & OBJECTIVE: Induction chemotherapy play an important role in treatment of the patients with tongue squamous cell carcinoma. This study was designed to evaluate the role of induction chemotherapy with single agent bleomycin A5 in treating stage T2 tongue squamous cell carcinoma. METHODS: The authors retrospectively analyzed the influence of surgery and induction chemotherapy with single agent bleomycin A5 plus surgery on survival rate and locoregional control among 72 patients with tongue squamous cell carcinoma. RESULTS: The 5-year survival rates were 81.46% and 57.14% respectively for the group of surgery alone and the group of induction chemotherapy plus surgery, the difference between the two groups were significant (P = 0.0229). The rates of locoregional recurrence were 22.2%, 33.3% and the medial time of recurrence was 20, 24 months respectively in the two groups. For the patients in stage II and stage III plus stage IV, there was no difference between the two groups for the 5-year survival rate (P = 0.0949; P = 0.0739). For the patients in stage III plus stage IV, the rates of locoregional recurrence were 12.5%, 35.7% and the medial time of recurrence was 12, 12.8 months, respectively, in the two groups. CONCLUSIONS: It has no significant role in treatment of the patients with stage T2 tongue squamous cell carcinoma for single agent bleomycin A5. Induction chemotherapy using single agent bleomycin A5 did not improve the 5-year survival rate for early or late primary lesions. The impact on the control rate of locoregional recurrence would be studied further for single agent bleomycin A5.

Adult↗
PubMed2003

[The effect of murine interferon-gamma transgene expression on bleomycin-induced pulmonary fibrosis in mice].

OBJECTIVE: To investigate the effect of murine interferon-gamma (IFN-gamma) transgene expression on bleomycin-induced pulmonary fibrosis in mice. METHODS: 6 - 8 week aged pathogen-free male ICR mice were treated with bleomycin (3 mg/kg weight in 70 micro l) by intranasal instillation on day 0 in the model group. Adenoviral vector with murine IFN-gamma cDNA (AdCMVmIFN-gamma) 5 x 10(8) plague forming unit (pfu) was administrated via nastril instillation 48 h before bleomycin treatment in the preventive therapeutic group, but 72 h after bleomycin treatment in the therapeutic group. Mice treated with a same volume of normal saline (NS) and a same dosage of sham recombinant adenoviruses (AdCMVNull) served as controls. The animals were weighted on day 0, 7, 14, and sacrificed on day 14. Bronchial alveolar lavage fluid (BALF) and lungs were recovered. The right lung was stained with either hematoxylin-eosin or masson. The left lung was weighted, and its content of hydroxyproline (HYP) was measured by HCl acid hydrosis method. The IFN-gamma concentration in BALF was determined with enzyme-linked immunosorbent assay. RESULTS: The concentrations of IFN-gamma in BALF from the AdCMVmIFN-gamma treated groups were remarkably increased, (21,250 +/- 6,497) pg/ml and (21,000 +/- 5,451) pg/ml in the IFN-gamma transgenetic preventive therapeutic group and the therapeutic group respectively. IFN-gamma was undetectable in BALF from other groups. Mice in the two groups treated with AdCMVmIFN-gamma had statistically significant weight loss (P < 0.05), higher HYP content (P < 0.05), and tended to have more severe alveolitis and pulmonary fibrosis (P = 0.07) as compared with those in other groups. CONCLUSIONS: (1) mIFN-gamma could be overexpressed in airway and alveolar epithelium by locally administrated AdCMVmIFN-gamma. (2) Early mIFN-gamma transgene expression via adenoviral vector in this bleomycin model aggravated alveolitis and fibrosis to some degree.

Adenoviridae↗
PubMed1992

Reaction of Co(II)bleomycin with dioxygen.

The reaction of Co(II)bleomycin with dioxygen has been investigated. Dioxygen binds to the Co(II) complex within the time of mixing according to electron spin resonance and uv-visible spectroscopy and dioxygen analysis. Then, two dioxygenated cobalt centers react, releasing 1 mol of O2 and forming an intermediate characterized by a few highly shifted 1H NMR resonances and loss of the ESR spectrum. This is thought to be a dioxygen-bridged dimer of cobalt bleomycin molecules. Time-dependent absorbance and dioxygen measurements yield the same second order rate constant for this step of the reaction. According to uv-visible and NMR spectral analysis, the intermediate decays into diamagnetic products in a first order rate process. High performance liquid chromatography and 1H NMR studies demonstrate that the product contains two bleomycin species of equal concentration. One component is Co(III)bleomycin, designated Form II. The other is the peroxide adduct of Co(III)bleomycin, Form I, as determined by direct determination of hydrogen peroxide, which is slowly released from the product at low pH. In contrast, hydrogen peroxide is readily detected during the reaction of Co(II)Blm with O2. In isolation, Form I is unstable at pH 7 and is converted within 24 h into a mixture of Form I and Form II.

Bleomycin↗
PubMed1992

Bleomycin pharmacology: mechanism of action and resistance, and clinical pharmacokinetics.

Bleomycin is a glycopeptide antibiotic with a unique mechanism of antitumor activity. The drug binds to guanosine-cytosine-rich portions of DNA via association of the "S" tripeptide and by partial intercalation of the bithiazole rings. A group of five nitrogen atoms arranged in a square-pyramidal conformation binds divalent metals including iron, the active ligand, and copper, an inactive ligand. Molecular oxygen, bound by the iron, can produce highly reactive free radicals and Fe(III). The free radicals produce DNA single-strand breaks at 3'-4' bonds in deoxyribose. This yields free base propenals, especially of thymine: cytotoxicity is cell-cycle-phase specific for G2 phase. In humans, bleomycin is rapidly eliminated primarily by renal excretion. This accounts for approximately half of a dose. In patients with renal compromise or extensive prior cisplatin therapy, the drug half-life can extend from 2 to 4 hours up to 21 hours. Thus, dose adjustments are needed when creatinine clearance is less than or equal to 3N mL/min. Finally, resistance to bleomycin in normal tissues can be correlated with the presence of a bleomycin hydrolase enzyme, which is in the cysteine proteinase family. The enzyme replaces a terminal amine with a hydroxyl, thereby inhibiting iron binding and cytotoxic activity. The low concentration of enzyme in the skin and lung may explain the unique sensitivity of these tissues to bleomycin toxicity. However, correlation of hydrolase levels with tumor cell sensitivity has thus far been negative.

Bleomycin↗
PubMed2004

[Regulative effect of STAT1 on inflammation of lung tissue in bleomycin-induced rat interstitial pulmonary fibrosis].

OBJECTIVE: To investigate the role of signal transducer and activator of transcription 1 (STAT1) in alveolar macrophage (AM) in bleomycin-induced rat pulmonary fibrosis. METHODS: Fifty adult female Wistar rats were randomly divided into two groups. The rats of BLM group were intratracheally instilled with bleomycin (BLM), and those of the control group with normal saline(NS). The kinetic change of STAT1 activation and the intercellular adhesion molecule-1 (ICAM-1) expression in AM were examined. RESULTS: STAT1 was slightly activated in AM of NS group. After bleomycin treatment, the STAT1 activation of AM significantly increased on day 1, reached the peak value on day 7, and then gradually decreased, yet it remained significantly above the value of the NS group on day 28 (P < 0.05). There were a few positive staining cells for ICAM-1 expression in AM of NS group. After intratracheal instillation of bleomycin, the number of positive staining cells for ICAM-1 expression significantly increased on day 1, reached the peak value on day 7, gradually decreased from then on, but still it was higher than that of the NS group on day 28 (P < 0.05). There was a significant correlation between STAT1 activation and ICAM-1 expression in AM (r = 0.913, P < 0.01); moreover, ICAM-1 expression in AM was significantly correlated with the degree of inflammation in lung tissue (r = 0.947, P < 0.01). CONCLUSION: STAT1 was found abnormally activated in AM in bleomycin-induced rat interstitial pulmonary fibrosis (IPF). The abnormal STAT1 activation may play a role in the pathogenesis of acute alveolitis and pulmonary fibrosis.

Animals↗
PubMed2005

[The pivotal role of CXCR3 in the pathogenesis of bleomycin-induced pulmonary fibrosis].

OBJECTIVE: To investigate the contribution of chemokine receptor-CXCR3 to the fibrotic disease process induced by bleomycin in CXCR3 gene deficient mice. METHODS: Sixty-two CXCR3 knock-out mice with C57Bl/6 background were established by gene targeting. Forty-eight sex-, age- and weight-matched C57Bl/6 mice were challenged by injection of bleomycin via trachea. Lung tissue was stained with HE and Masson-trichrome methods. Lung hydroxyproline content was evaluated. Bronchoalveolar lavage was performed using PBS, and the cell number and differentials were counted by Diff-Quick staining. TNF-alpha, IL-5 and TGF-beta in the lung homogenate were measured by ELISA. T lymphocytes were analyzed by FACScan. Unpaired t test was explored to compare the difference between two groups. RESULTS: On day 14 after bleomycin injection, CXCR3 knockout mice were protected from BLM-induced lung injury and fibrosis as evidenced by less inflammatory cells in the lung interstitium and hydroxyproline content in the lung tissue compared to the wild type littermates [3.92 +/- 0.37 vs 5.33 +/- 0.34, P < 0.05; (67.0 +/- 24.2) microg/left lung vs (211.5 +/- 24.2) microg/left lung, P < 0.01]. On day 7 after bleomycin administration, there was less infiltration of neutrophils, lymphocytes and CD(4)(+) T lymphocytes into lung tissue in CXCR3 knockout mice than those in the wild-type mice [(3.25 +/- 0.61) x 10(5) vs (6.13 +/- 0.86) x 10(5), P < 0.05]; [(8.15 +/- 1.96) x 10(5) vs (13.48 +/- 1.47) x 10(5), P < 0.05]; [(9.00 +/- 1.00) x 10(4) vs (15.60 +/- 2.00) x 10(4), P < 0.05]. Lower level of fibrogenic cytokine release, including the altered production of TNF-alpha and IL-5, was seen in CXCR3 knockout mice compared to the wild type mice [(1,023 +/- 113) microg/L vs (1,530 +/- 178) microg/L, P < 0.05; (403 +/- 50) microg/L vs (755 +/- 95) microg/L, P < 0.05] on day 7 postbleomycin injection, whereas TGF-beta level was decreased significantly in CXCR3 knockout mice compared to the wild-type mice on day 14 postbleomycin administration [(2,211 +/- 289) microg/L vs (5,388 +/- 1,071) microg/L, P < 0.05]. CONCLUSIONS: These data imply that CXCR3 signaling promotes CD(4)(+) T-cell recruiting and initiates fibrogenic cytokine cascade following intratracheal bleomycin administration and indicate that CXCR3 might be a therapeutic target for pulmonary fibrosis treatment.

Animals↗
PubMed2005

[Bleomycin induced flagellate erythema].

Bleomycin is an antibiotic with antineoplastic pro prieties. It is used in the traitement of many syndromes. The cutaneous toxicity of bleomycin includes many alteration. We report a case of flagellate erythema following the administration of bleomycin in a 57-year-old women with Kaposi sarcoma. She developped linear lesions 6 days after the first dose of bleomycin. Flagellate erythema is a specific reaction to bleomycin therapy wich occurs in susceptible individuals independently of dose, route of administration and type of malignant disease treated. Its occurs in 10 to 35% of the treated patients.

Antimetabolites, Antineoplastic↗
PubMed2006

Intralesional bleomycin for warts: a review.

Intralesional bleomycin has been used for the treatment of warts since the 1970s. Currently, there is a limited amount of evidence from randomized placebo-controlled trials comparing intralesional bleomycin with other local treatments for warts. Numerous reports have been published on the use of intralesional bleomycin for the treatment of recalcitrant warts with cure rates ranging from 14% to 99%. The majority of the data suggests that bleomycin is effective in over two-thirds of the reported cases with minimal side effects. In this paper, we review the mechanism of action, pharmacokinetics, safety profile, supply and storage, dosage scheme, techniques for administration, and efficacy of intralesional bleomycin for the treatment of warts.

Antibiotics, Antineoplastic↗
PubMed1990

Bleomycin-induced DNA damage and repair in human cells permeabilized with lysophosphatidylcholine.

We have examined bleomycin-induced DNA damage and repair in confluent human fibroblasts that were reversibly permeabilized to small molecules (e.g., deoxynucleotide triphosphates and trypan blue) by a short exposure to 80 micrograms/ml lysophosphatidylcholine. We found that this treatment dramatically increases the dose effectiveness of bleomycin in inducing DNA strand breaks and DNA repair synthesis in these cells. For example, when intact cells (not treated with lysophosphatidylcholine) were incubated with 100 micrograms/ml bleomycin, only about 5% of the cell population was observed to have undergone measurable DNA repair synthesis (by autoradiography). On the other hand, when these cells were reversibly permeabilized with lysophosphatidylcholine before treatment, we observed significant repair synthesis in greater than 80% of the cells using a bleomycin dose of only 5 micrograms/ml. Furthermore, sufficient levels of single- and double-strand breaks were introduced into nucleosome linker DNA of permeabilized cells to yield a nucleosomal repeat pattern in alkaline and neutral agarose gels. However, no change in the amount of DNA less than 23 kilobases was observed on these gels when intact cells were incubated with bleomycin.

Autoradiography↗
PubMed1990

A role for the metal binding domain in determining the DNA sequence selectivity of Fe-bleomycin.

Previous studies of Fe-bleomycin-mediated DNA cleavage have established that the bithiazole moiety + C-terminal substituent of bleomycin are required for DNA binding, while the metal binding domain is responsible for O2 activation. Although recent studies have indicated that the metal binding domain also participates in DNA unwinding, and in determining the sequence and strand selectivity of DNA cleavage, no study has defined the structural domain that bears primary responsibility for the observed pattern of bleomycin-mediated DNA degradation. Presently, by the use of four synthetic analogs of bleomycin demethyl A2 having the functional domains connected by rigid spacers of varying lengths, the source of DNA cleavage specificity has been determined. When the four analogs cleaved 242- and 127-base pair 5'-32P-end-labeled DNA restriction fragments containing isolated Fe-bleomycin cleavage sites, all four produced cleavage at the same preferred sites. Because the (oligo)glycine spacers altered the distance between the domains by as much as 14 A, the identical cleavage patterns argue that the primary determinant of sequence specificity for these analogs is the metal binding domain.

Base Sequence↗
PubMed1990

[Procoagulant activity of alveolar macrophages in bleomycin-induced lung fibrosis in rats].

Interstitial and intraalveolar fibrin deposition is a prominent feature in adult respiratory distress syndrome and is also observed in the inflammatory phase of interstitial lung disease (ILD). It is suggested that the coagulation abnormality in these disorders may be implicated in the pathogenesis of subsequent fibrosis of the lung. In this study, we examined the procoagulant activity (PCA) of alveolar macrophages during the development of bleomycin-induced lung fibrosis in rats. The PCA of alveolar macrophages was significantly increased at 2, 7 and 14 days after the intratracheal administration of bleomycin compared with that of control rats. The greatest PCA was observed at 7 days after the bleomycin injection, the inflammatory phase in the development of lung fibrosis. Increased PCA returned to the normal value at 21 days, while the fibrotic process advanced and the collagen content increased in the lung. Alveolar macrophages at 7 days after the administration of bleomycin or saline were separated into five density fractions on discontinuous Percoll gradients. The increase in the percentage of low-density macrophages was observed in bleomycin-injected rats. The greatest PCA was demonstrated in the lowest-density fraction (specific gravity less than 1.030), while reduced activities were observed in the higher-density fractions, in each group. The increased PCA of alveolar macrophages during lung injury was due in part to the increase of low-density subpopulation, which had greater PCA, although the fibrin deposition in the development of lung fibrosis remained to be defined, the increase of coagulation pathways may contribute to the progression of interstitial fibrotic lung diseases.

Animals↗
PubMed2006

CXC chemokine receptor 3 modulates bleomycin-induced pulmonary injury via involving inflammatory process.

OBJECTIVE: To investigate the role of CXC chemokine receptor 3 (CXCR3) in bleomycin-induced lung injury by using CXCR3 gene deficient mice. METHODS: Sex-, age-, and weight-matched C57BL/6 CXCR3 gene knockout mice and C57BL/6 wide type mice were challenged by injection of bleomycin via trachea. Lung tissue was stained with HE method. Airway resistance was measured. Bronchoalveolar lavage (BAL) was performed using phosphate buffered saline twice, cell number and differentials were counted by Diff-Quick staining. Interleukin (IL)4, IL-5, IL-12p40, and interfon-y in BAL fluid and lung homogenate were measured by enzyme-linked immunosorbent assay. Unpaired t test was explored to compare the difference between two groups. RESULTS: On day 7 after bleomycin injection via trachea, CXCR3 knockout mice were protected from bleomycin-induced lung injury as evidenced by fewer accumulation of inflammatory cells in the airway and lung interstitium compared with their wild type littermates (P < 0.05). Airway resistance was also lower in CXCR3 knockout mice compared with wild type mice (P < 0.01). Significantly lower level of inflammatory cytokines release, including the altered production of IL-4 and IL-5 both in BAL fluid and lung tissue was seen in CXCR3 knockout mice than in wild type mice (both P<0.05). CONCLUSION: CXCR3 signaling promotes inflammatory cells recruiting and initiates inflammatory cytokines cascade following endotracheal bleomycin administration, indicating that CXCR3 might be a therapeutic target for pulmonary injury.

Airway Resistance↗
PubMed1991

[Mechanism of enhancement of bleomycin A5 antitumor activity by verapamil].

The mechanism of enhancement of Bleomycin A5 antitumor activity by verapamil was explored by flow cytometry and tracing the radiolabelled bleomycin A5 in vivo. Verapamil was found to increase the G2 blocking effect of bleomycin A5 prominently in mouse S-180 and human HEP-2 cell lines. The distribution of 57Co-bleomycin A5 in mice bearing S-180 sarcoma was changed by verapamil and accumulation of the drug in tumor was increased. In contrast, the labelled drug in the lung was decreased. It seems that the effects of verapamil in enhancing the antitumor activity of bleomycin A5 are to increase the accumulation of the drug in tumor cells and enhance the G2 blocking effect of the drug in cell cycle.

Animals↗