Dactinomycin D dược chất kháng A549

A549 subclones demonstrate heterogeneity in toxicological sensitivity ...

Dactinomycin D

From Wikipedia, the free encyclopedia

Dactinomycin

Clinical data
Trade names	Cosmegen
AHFS/Drugs.com	Monograph
MedlinePlus	a682224
Pregnancy category	AU: D US: D (Evidence of risk)
Routes of administration	IV
ATC code	L01DA01 (WHO)
Legal status
Legal status	AU: S4 (Prescription only) CA: ℞-only UK: POM (Prescription only) US: ℞-only
Pharmacokinetic data
Protein binding	5%
Biological half-life	36 hours
Identifiers
IUPAC name[show]
Synonyms	Actinomycin D 2-Amino- 4,6-dimethyl- 3-oxo- 3H-phenoxazine- 1,9-dicarboxylic acid bis- [(5,12-diisopropyl- 9,13,16-trimethyl- 4,7,11,14,17-pentaoxo- hexadecahydro- 10-oxa- 3a,6,13,16-tetraaza- cyclopentacyclohexadecen- 8-yl)- amide]
CAS Number	50-76-0
PubChem CID	2019
DrugBank	DB00970
ChemSpider	10482167
UNII	1CC1JFE158
KEGG	C06770
ChEBI	CHEBI:27666
ChEMBL	CHEMBL1554
NIAID ChemDB	009885
ECHA InfoCard	100.000.058
Chemical and physical data
Formula	C62H86N12O16
Molar mass	1255.42 g/mol
InChI[show]
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Dactinomycin, also known as actinomycin D, is a chemotherapy medication used to treat a number of types of cancer. This includes Wilms tumor, rhabdomyosarcoma, Ewing's sarcoma, trophoblastic neoplasm, testicular cancer, and certain types of ovarian cancer. It is given by injection into a vein.^[1]

Most people develop side effects. Common side effects include bone marrow suppression, vomiting, mouth ulcers, hair loss, liver problems, infections, and muscle pains. Other serious side effects include future cancers, allergic reactions, and tissue death at the site of injection. Use in pregnancy may harm the baby.^[1] Dactinomycin is in the cytotoxic antibiotic family of medications.^[2] It is believed to work by blocking the creation of RNA.^[1]

Dactinomycin was approved for medical use in the United States in 1964.^[1] It is on the World Health Organization's List of Essential Medicines, the most effective and safe medicines needed in a health system.^[3] The wholesale cost in the developing world is about 24.73 USD per 500 mcg vial.^[4] It is produced from bacteria Streptomyces parvullus.^[1]

Contents

  [hide] 

• 1Medical use
• 2Side effects
• 3Mechanism
• 4History
• 5Research use
• 6References
• 7External links

Medical use[edit]

Actinomycin is a clear, yellow liquid administered intravenously and most commonly used in treatment of a variety of cancers, including:

• Gestational trophoblastic neoplasia^[5]
• Wilms' tumor^[6]
• Rhabdomyosarcoma^[7]
• Ewing's sarcoma^[8]
• Malignant hydatidiform mole^[9]

Sometimes it will be combined with other drugs in chemotherapy regimens, like the VAC regimen (with vincristine and cyclophosphamide) for treating rhabdomyosarcoma and Ewing's sarcoma.

It is also used as a radiosensitizer in adjunct to radiotherapies, since it can increase the radiosensitivity of tumor cells by inhibiting repair of sublethal radiation damage and delay the onset of the compensatory hyperplasia that occurs following irradiation.^[10]

Side effects[edit]

Common adverse drug reaction includes bone marrow suppression, fatigue, hair loss, mouth ulcer, loss of appetite and diarrhea. Actinomycin is a vesicant, if extravasation occurs.

Mechanism[edit]

In cell biology, actinomycin D is shown to have the ability to inhibit transcription. Actinomycin D does this by binding DNA at the transcription initiation complex and preventing elongation of RNA chain by RNA polymerase.^[11]

History[edit]

Actinomycin D was the first antibiotic shown to have anti-cancer activity.^[12] It was first isolated by Selman Waksman and his co-worker H. Boyd Woodruff in 1940.^[13] It was approved by the U.S. Food and Drug Administration (FDA) on December 10, 1964 and launched by Merck Sharp and Dohme under the trade name Cosmegen.

Research use[edit]

Because actinomycin can bind DNA duplexes, it can also interfere with DNA replication, although other chemicals such as hydroxyurea are better suited for use in the laboratory as inhibitors of DNA synthesis.

Actinomycin D and its fluorescent derivative, 7-aminoactinomycin D (7-AAD), are used as stains in microscopy and flow cytometry applications. The affinity of these stains/compounds for GC-rich regions of DNA strands makes them excellent markers for DNA. 7-AAD binds to single stranded DNA; therefore it is a useful tool in determining apoptosis and distinguishing between dead cells and live ones.^[14]

A549 Cell

A549 Cell Line Transfection Protocol Reagent Method

A549 Cell Line Transfection, Protocol, Kits and Reagents

Copyright picture from Altogen.com. Reproduced with permission from Altogen Biosystems.

A549 Cell Line Origin

The A549 cell line was first developed in 1972 by D.J. Giard, et al., through the removal and culturing of cancerous lung tissue in the explanted tumor of 58-year-old Caucasian male.  The cells produced were adenocarcinomic alveolar basal epithelial cells with a modal chromosome number of 66.  This type of cell in a normal lung is squamous and performs the task of diffusing water, electrolytes and other substances across the surface of the alveoli.

A549 Cytogenetic Information

The cell line is hypotriploid with a modal chromosome number of 66, which occurs in 24% of cells. Modal numbers of 64 and 67 is relatively common with higher ploidies occurring at an infrequent rate (0.4%).

Morphology and Characteristics of A549 Cells

A549 cells have been well characterized over the years and are a valuable tool to researchers that routinely use them as in vitro and in vivo models.  These cells are squamous in nature and are responsible for the diffusion of substances such as water and electrolytes across the alveoli of lungs.  These cells are human alveolar basal epithelial cells and grow adherently as a monolayer in vitro.

A549 cells are positive for keratin, as is evidenced by immunoperoxidase staining.  The cells are able to synthesize lecithin and contain a high percentage of desaturated fatty acids, which are utilized by the cytidine-diphosphocholine pathway and important for the maintenance of membrane phospholipids in cells.

A549 Cell Line Derived Xenograft Mouse Model

The A549 non-small cell lung cancer (nsclc) cell line is cultured and then inoculated in mice to create the A549 CDX mouse model (cell line derived xenograft).  The A549 CDX model is one of the most highly utilized xenograft lung cancer models used by researchers for studying SoC (standard of care) and novel therapeutics (i.e. gefitinib, erlotinib, paclitaxel. lapatinib) due to overexpression of HER-2 and EGFR receptors.  Typical end of study results are comprised of tumor volume measurements, body weight tracking or animal survival.

The following options are typically available for an A549 CDX xenograft model:

• Dosing frequency and duration of dose administration
• A549 Tumor Growth Delay
• A549 Tumor Growth Inhibition
• Dosing routes:
  • Intravenous
  • Intratracheal
  • continuous infusion
  • intraperitoneal
  • intratumoral
  • oral gavage
  • topical
  • intramuscular
  • subcutaneous
  • intranasal
  • cutting-edge micro-injection techniques and pump-controlled IV injection
• A549 tumor immunohistochemistry
• Cell engraftment sites
  • orthotopic transplantation
  • tail vein injection
  • left ventricular injection for metastasis studies
  • injection into mammary fat pad
  • intraperitoneal injection
• Blood chemistry analysis
• Toxicity and survival (optional: performing a broad health observation program)
• Gross necropsies and histopathology
• Imaging studies: Fluorescence-based whole body imaging, MRI
• Positive control group employing cyclophosphamide, at a dosage of 50 mg/kg administered by intramuscular injection to the control group daily for the study duration
• Lipid distribution and metabolic assays

Publications

• Chemokine production by A549 cells in response to Mycobacterium tuberculosis: In this study, A549 cells were infected with several strains of M. tuberculosis and then their chemokine production was measured. In addition, the intracellular growth of the A549 cells was measured and compared with the chemokine production. LINK: http://iai.asm.org/content/66/3/1121.long
• Observation of differentiation in A549 cells: Monolayer cultures of A549 cells were maintained for up to three weeks, and examined using an immunoperoxidase technique. This technique used antibodies to detect surface-associated glycoproteins, which bound differently to certain A549 cells, indicating localization of the glycoproteins. LINK: http://www.ncbi.nlm.nih.gov/pubmed/6092046

A549 cell

From Wikipedia, the free encyclopedia

A549 cells under DIC microscopy, from a 3-4 days old culture, showing an abundance of intercellular connections, including possible cytonemes, filopodia and other epithelial bridges. (These cells have endocytosed 25x73 nm colloidal gold nanorods.)

A549 cells are adenocarcinomic human alveolar basal epithelial cells. The A549 cell line was first developed in 1972 by D. J. Giard, et al. through the removal and culturing of cancerous lung tissue in the explanted tumor of a 58-year-old caucasian male.^[1][2] In nature, these cells are squamous and responsible for the diffusion of some substances, such as water and electrolytes, across the alveoli of lungs. If A549 cells are cultured in vitro, they grow as monolayer cells, adherent or attaching to the culture flask.^[1] The human alveolar epithelial cell line A549 may be anchored or suspended in a solution in vitro.

Another characteristic of these cells is that they are able to synthesize lecithin and contain high level of unsaturated fatty acids, which are important to maintain the membrane phospholipids in cells.^[1] A549 cell line are widely used as an in vitro model for a type II pulmonary epithelial cell model for drug metabolism and as a transfection host.^[3][4]