Carboplatin

Carboplatin (NSC 241240) is a DNA synthesis inhibitor which binds to DNA, inhibits replication and transcription and induces cell death. Carboplatin (NSC 241240) is a derivative of cisplatin and a potent anti-cancer agent.

Signaling Pathways >> Autophagy >> Autophagy

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA Alkylator/Crosslinker

Signaling Pathways >> Cell Cycle/DNA Damage >> DNA/RNA Synthesis

Research Areas >> Cancer

DNA Alkylator[1]

Carboplatin is an antitumor agent, with an increased DNA-binding activity in the presence of nucleophiles and human breast cancer MCF-7 cell cytoplasmic extracts[1]. Carboplatin is less cytotoxic to human ovarian cells such as A2780, SKOV3, IGROV1 and HX62 than 17-AAG, with IC50s of 6.177, 12.442, 2.233 and 116.068 μM, respectively. Moreover, Carboplatin does not affect HSP90 or change the activity of 17-AAG to inhibit HSP90[2]. Carboplatin reduces the viability of Brca1 (IC50, 3.4 μM) and Brca2 cells (IC50, 1.9 μM). Carboplatin (25 μM) combined with ABT-888 also shows an apoptotic effect in BRCA1 cells[3].

Carboplatin (60 mg/kg, i.p.) shows a modest effect on the tumor, but significantly inhibits tumor growth in combination with 17-AAG in mice bearing A2780 human ovarian cancer xenografts[2]. Carboplatin (25 mg/kg, p.o.) combined with ABT-888 delays tumor growth in Brca2 xenografts[3].

Exponentially growing A2780 cells are plated in 96 well microtitre plates. For experiments studying the effect of sequence of exposure to 17-AAG or Carboplatin, cells are exposed to increasing concentrations of 17-AAG or Carboplatin for 24 h. A period of 24-h exposure to the first agent is chosen so that the A2780 cells will be exposed to the first drug for at least one doubling time (18-24 h). The cells are then washed with sterile phosphate buffered saline and the medium is replenished. Following this, the second drug (to which the cells are not exposed to in the first 24 h) or medium is added for 96 h. SRB assays are carried out. All experiments are carried out in triplicate[2].

Mice[2] The A2780 human ovarian cancer cell line is grown as a subcutaneous xenograft in female athymic NCr nude mice (nu/nu) by injecting 4 × 106 cells in each flank. Mice with established tumors corresponding to a mean volume of 0.69 mm3 are randomized into groups (six animals each) for treatment with either control vehicle (43% ethanol, 33% polypropylene glycol and 24% cremaphor diluted 1:7 with sterile water) days 1-4, 17-AAG (80 mg/kg intraperitonially, days 1-4), Carboplatin (60 mg/kg IP day 0) or a combination of 17-AAG (80 mg/kg IP days 1-4) and Carboplatin (60 mg/kg IP day 0). Tumor growth is assessed three times weekly and tumor volumes are calculated according to a validated formula: volume = 4.19 × (a/4 + b/4)3, where a is the longer and b the shorter diameter. Tumor volumes are then expressed as a proportion of the volume at the start of treatment (relative tumor volume)[2].

[1]. Natarajan G, et al. Increased DNA-binding activity of cis-1,1-cyclobutanedicarboxylatodiammineplatinum(II) (carboplatin) in the presence of nucleophiles and human breast cancer MCF-7 cell cytoplasmic extracts: activation theory revisited. Biochem Pharmacol. 1999 Nov 15;58(10):1625-9.

[2]. Banerji U, et al. An in vitro and in vivo study of the combination of the heat shock protein inhibitor 17-allylamino-17-demethoxygeldanamycin and carboplatin in human ovarian cancer models. Cancer Chemother Pharmacol. 2008 Oct;62(5):769-78.

[3]. Clark CC, et al. Enhancement of synthetic lethality via combinations of ABT-888, a PARP inhibitor, and carboplatin in vitro and in vivo using BRCA1 and BRCA2 isogenic models. Mol Cancer Ther. 2012 Sep;11(9):1948-58.

[4]. Dela Cruz FS, et al. A case study of an integrative genomic and experimental therapeutic approach for rare tumors: identification of vulnerabilities in a pediatric poorly differentiated carcinoma. Genome Med. 2016 Oct 31;8(1):116.

Cycloheximide | Actinomycin D | alpha-Amanitin | Anisomycin | SCR7 | CX-5461 | Calicheamicin | LMI070 | COH29 | Triciribine | Folic Acid | Halofuginone | RG7800 | Carmustine | ML216

MOLECULAR FORMULA :

C6-H12-N2-O4-Pt

MOLECULAR WEIGHT :

371.29

WISWESSER LINE NOTATION :

L4TJ AVQ AVQ &Z-PT-Z

HEALTH HAZARD DATA

ACUTE TOXICITY DATA

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Oral

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

343 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Subcutaneous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

72 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

60900 ug/kg

TOXIC EFFECTS :

Sense Organs and Special Senses (Eye) - effect, not otherwise specified Gastrointestinal - hypermotility, diarrhea Nutritional and Gross Metabolic - weight loss or decreased weight gain

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intraperitoneal

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

118 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

89360 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Rodent - mouse

DOSE/DURATION :

180 mg/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

>31200 ug/kg

TOXIC EFFECTS :

Details of toxic effects not reported other than lethal dose value

TYPE OF TEST :

LD50 - Lethal dose, 50 percent kill

ROUTE OF EXPOSURE :

Unreported

SPECIES OBSERVED :

Mammal - species unspecified

DOSE/DURATION :

158 mg/kg

TOXIC EFFECTS :

Tumorigenic - active as anti-cancer agent

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Rodent - rat

DOSE/DURATION :

70 mg/kg/2W-I

TOXIC EFFECTS :

Lungs, Thorax, or Respiration - changes in lung weight Endocrine - changes in spleen weight Blood - changes in platelet count

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

140 mg/kg/26W-I

TOXIC EFFECTS :

Blood - normocytic anemia Blood - changes in bone marrow (not otherwise specified) Blood - changes in leukocyte (WBC) count

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

SPECIES OBSERVED :

Mammal - dog

DOSE/DURATION :

60 mg/kg/5D-I

TOXIC EFFECTS :

Gastrointestinal - alteration in gastric secretion Gastrointestinal - other changes Blood - hemorrhage

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

24 mg/kg

SEX/DURATION :

female 6-9 day(s) after conception

TOXIC EFFECTS :

Reproductive - Fertility - pre-implantation mortality (e.g. reduction in number of implants per female; total number of implants per corpora lutea) Reproductive - Effects on Embryo or Fetus - fetotoxicity (except death, e.g., stunted fetus) Reproductive - Effects on Embryo or Fetus - fetal death

TYPE OF TEST :

TDLo - Lowest published toxic dose

ROUTE OF EXPOSURE :

Intravenous

DOSE :

24 mg/kg

SEX/DURATION :

female 6-9 day(s) after conception

TOXIC EFFECTS :

Reproductive - Specific Developmental Abnormalities - Central Nervous System Reproductive - Specific Developmental Abnormalities - body wall Reproductive - Specific Developmental Abnormalities - musculoskeletal system

TYPE OF TEST :

Micronucleus test

TYPE OF TEST :

DNA damage

TYPE OF TEST :

DNA inhibition

TYPE OF TEST :

Mutation test systems - not otherwise specified

TYPE OF TEST :

Cytogenetic analysis

MUTATION DATA

TYPE OF TEST :

Morphological transformation

TEST SYSTEM :

Rodent - hamster Kidney

DOSE/DURATION :

25 umol/L

REFERENCE :

EJCODS European Journal of Cancer and Clinical Oncology. (Pergamon Press, c/o Elsevier Science, 660 White Plains Rd., Tarrytown, NY 10591) V.17(7)- 25, 1981-89. For publisher information, see EJCAEL Volume(issue)/page/year: 25,27,1989 *** REVIEWS *** TOXICOLOGY REVIEW JPMSAE Journal of Pharmaceutical Sciences. (American Pharmaceutical Assoc., 2215 Constitution Ave., NW, Washington, DC 20037) V.50- 1961- Volume(issue)/page/year: 65,315,1976