Carboplatin (formerly known as JM-8, CBDCA, NSC-241240; Paraplat; Paraplatin; Blastocarb; Carboplat; Carbosin; Carbosol; Carbotec; Displata; Ercar) is an approved anticancer drug that acts as a DNA synthesis inhibitor by binding to DNA (DNA alkylator) and interfering with the cell's repair mechanism in cancer cells. It is used to treat a few types of cancer, primarily head, neck, and ovarian cancers. It undergoes intracellular activation to generate reactive platinum complexes that attach to nucleophilic sites in DNA, including GC-rich regions, to create DNA-protein cross-links as well as intrastrand and interstrand cross-links. These effects of carboplatin on DNA and proteins lead to cell growth inhibition and apoptosis.
Physicochemical Properties
| Molecular Formula | C6H12N2O4PT | |
| Molecular Weight | 371.25 | |
| Exact Mass | 371.044 | |
| Elemental Analysis | C, 19.41; H, 3.26; N, 7.55; O, 17.24; Pt, 52.55 | |
| CAS # | 41575-94-4 | |
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| PubChem CID | 426756 | |
| Appearance | White solid powder | |
| Boiling Point | 366.4ºCat 760 mmHg | |
| Melting Point | 228-230ºC | |
| Flash Point | 189.6ºC | |
| LogP | 0.817 | |
| Hydrogen Bond Donor Count | 4 | |
| Hydrogen Bond Acceptor Count | 6 | |
| Rotatable Bond Count | 0 | |
| Heavy Atom Count | 13 | |
| Complexity | 177 | |
| Defined Atom Stereocenter Count | 0 | |
| SMILES | [Pt+2].O([H])C(C1(C(=O)O[H])C([H])([H])C([H])([H])C1([H])[H])=O.[N-]([H])[H].[N-]([H])[H] |
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| InChi Key | VSRXQHXAPYXROS-UHFFFAOYSA-N | |
| InChi Code | InChI=1S/C6H8O4.2H2N.Pt/c7-4(8)6(5(9)10)2-1-3-6;;;/h1-3H2,(H,7,8)(H,9,10);2*1H2;/q;2*-1;+2 | |
| Chemical Name | azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+) | |
| Synonyms | JM-8; NSC-241240; JM8; NSC241240; 41575-94-4; Paraplatin; Cbdca; Carboplatinum; MFCD00070464; NSC-241240; cis-(1,1-Cyclobutanedicarboxylato)diammineplatinum(II); JM 8; NSC 241240; CBDCA; Carboplatin Hexal; Carboplatino; US trade names: Paraplat; Paraplatin; Foreign brand names: Blastocarb; Carboplat; Carbosin; Carbosol; Carbotec; Displata; Ercar; Nealorin; Novoplatinum; Paraplatin AQ; Paraplatine; Platinwas; Ribocarbo | |
| HS Tariff Code | 2931.90.9051 | |
| Storage |
Powder-20°C 3 years 4°C 2 years In solvent -80°C 6 months -20°C 1 month Note: This product requires protection from light (avoid light exposure) during transportation and storage. |
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| Shipping Condition | Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs) |
Biological Activity
| Targets | DNA Alkylator | |
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| ln Vivo |
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| Cell Assay | 3-(4,5-dimethylthiazol-2yl)-2,5-diphenyltetrazolium bromide (MTT) assays: Ovarian cancer cells bearing the exponential growth markers A2780, SKOV3, IGROV-1, and HX62 are cultured in 96-well plates. To allow for three to four doubling times, a range of drug concentrations are added, and the plates are then incubated for 72 hours. Every experiment is run in three duplicates. Assays for sulforhodamine B (SRB): A2780 cells that are growing exponentially are plated in 96-well microtitre plates. In studies looking into concurrent exposure, cells are subjected to 96 hours of exposure to escalating concentrations of both medications. Cells are exposed to escalating concentrations of 17-AAG or carboplatin for a duration of 24 hours in order to conduct experiments examining the impact of exposure sequence. In order to give the A2780 cells at least one doubling time (18–24 hours), a 24-hour exposure period to the first agent was selected. The medium is then replaced after the cells are cleaned using sterile phosphate buffered saline. Subsequently, the medium or second medication, which the cells were not exposed to during the first 24 hours, is added and left for 96 hours. Every experiment is run in three duplicates. The well-established principles of the median effect analysis method are applied to the analysis of combination study results. An internal spreadsheet is used to calculate the combination's effects. | |
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| Toxicity/Toxicokinetics |
Effects During Pregnancy and Lactation ◉ Summary of Use during Lactation Most sources consider that mothers receiving antineoplastic therapy should not breastfeed, especially with alkylating agents such as carboplatin. It might be possible to breastfeed safely during intermittent therapy with an appropriate period of breastfeeding abstinence, but the duration of abstinence is not clear. Platinum in milk may increase with repeated courses of chemotherapy and the exact form(s), and toxicity of platinum excreted into breastmilk are also not known. The nursing infant would receive platinum compounds orally rather than intravenously and oral absorption of platinum compounds by infants is not known. It appears that it is not safe to breastfeed after carboplatin chemotherapy, and breastfeeding should probably be discontinued. Chemotherapy may adversely affect the normal microbiome and chemical makeup of breastmilk. Women who receive chemotherapy during pregnancy are more likely to have difficulty nursing their infant. ◉ Effects in Breastfed Infants Relevant published information was not found as of the revision date. ◉ Effects on Lactation and Breastmilk A telephone follow-up study was conducted on 74 women who received cancer chemotherapy at one center during the second or third trimester of pregnancy to determine if they were successful at breastfeeding postpartum. Only 34% of the women were able to exclusively breastfeed their infants, and 66% of the women reported experiencing breastfeeding difficulties. This was in comparison to a 91% breastfeeding success rate in 22 other mothers diagnosed during pregnancy, but not treated with chemotherapy. Other statistically significant correlations included: 1. mothers with breastfeeding difficulties had an average of 5.5 cycles of chemotherapy compared with 3.8 cycles among mothers who had no difficulties; and 2. mothers with breastfeeding difficulties received their first cycle of chemotherapy on average 3.4 weeks earlier in pregnancy. Of the 3 women who received a regimen containing the similar drug, cisplatin, 1 had breastfeeding difficulties. |
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| References |
[1]. Cancer Chemother Pharmacol . 2008 Oct;62(5):769-78. [2]. Clin Transl Oncol . 2011 Jan;13(1):43-9. [3]. Mol Cancer Ther . 2012 Sep;11(9):1948-58. [4]. Clin Cancer Res . 2004 Mar 1;10(5):1633-44. [5]. Anticancer Res . 2011 Sep;31(9):2713-22. [6]. Cancer Res . 2014 Jul 15;74(14):3913-22. [7]. Br J Cancer. 1995 Dec; 72(6): 1406–1411. |
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| Additional Infomation |
Carboplatin can cause developmental toxicity according to state or federal government labeling requirements. An organoplatinum compound that possesses antineoplastic activity. See also: Carboplatin (annotation moved to). Purpose: To study the interactions of the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygeldanamycin (17-AAG) and carboplatin in vitro and in vivo. Experimental design: The combination of 17-AAG and carboplatin on the growth inhibition of A2780, SKOV-3, IGROV-1 and HX62 human ovarian cancer cells was studied in vitro by MTT assays. The effect of the sequence of administration of both drugs was further investigated in A2780 cells by sulforhodamine B assays. The ability of 17-AAG to deplete HSP90 client proteins either alone or in combination with carboplatin was evaluated by western blotting. Tumor concentrations of 17-AAG and carboplatin alone or in combination in vivo were determined by validated liquid chromatography with ultraviolet detection and atomic absorption spectroscopy methods. The growth inhibitory effects of 17-AAG, carboplatin and the combination were studied in the A2780 xenograft model. Results: The combination index (CI) at fu(0.5) for 17-AAG plus carboplatin was 0.97 (+/-0.12 SD) when A2780 cells were exposed to carboplatin followed by 17-AAG indicating additivity. The addition of carboplatin did not alter the ability of 17-AAG to cause C-RAF, CDK4 and p-AKT depletion or HSP70 induction. Tumor 17-AAG and carboplatin concentrations were not significantly different in the single agent and combination arms. Tumor weights relative to controls on day 6 (T/C) were 67% for the carboplatin, 64% for the 17-AAG and 22% for the combination. Conclusion: In the specified sequences of drug exposure, 17-AAG and carboplatin have additive growth inhibitory effects in vitro and beneficial effects were seen with the combination in vivo. These findings form the basis for the possible evaluation of 17-AAG and carboplatin in a clinical trial. [1] Introduction: Chemotherapy for advanced well-differentiated carcinoids is characterised by low response rates and short duration of responses. The present study aimed to assess the in vitro activity of novel platinum-based chemotherapeutic drugs in combination with dichloroacetate (DCA), a sensitiser to apoptosis, against lung carcinoid cell lines. Methods: Three permanent cell lines (UMC-11, H727 and H835) were exposed to 14 different established cytotoxic drugs and the novel platinum-based compounds as satraplatin, JM118 and picoplatin in combination with DCA, and viability of the cells was measured using a tetrazoliumbased dye assay. Results: With exception of the highly chemoresistant UMC- 11 line, the carcinoid cell lines (H727, H835) were sensitive to the majority of chemotherapeutics in vitro. Among the platinum-based drugs, carboplatin and oxaliplatin showed highest efficacy. H835 cells growing as multicellular spheroids were 2.7-8.7-fold more resistant to picoplatin, satraplatin and its metabolite compared to single cell suspensions. DCA (10 mM) inhibited the growth of UMC- 11 cells by 22% and sensitised these highly resistant cells to carboplatin, satraplatin and JM118 1.4-2.4-fold. Conclusion: The highly resistant UMC-11 lung carcinoid cells are sensitive to carboplatin, oxaliplatin and the satraplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and pulmonary tumourlets, seems to increase chemoresistance markedly. The activity of carboplatin and JM118 is significantly and specifically increased in combination with the apoptosis sensitiser DCA that promotes mitochondrial respiration over aerobic glycolysis. In summary, among the novel platinum drugs satraplatin has the potential for treatment of lung carcinoids and DCA potentiates the cytotoxicity of selected platinum drugs.[2] Individuals with an inherited BRCA1 or BRCA2 mutation have an elevated risk of developing breast cancer. The resulting tumors typically lack homologous recombination repair as do a subset of sporadic tumors with acquired BRCA deficiency. Clinical responses to monotherapy with platinum drugs or poly PARP inhibitors (PARPi) have been shown for BRCA-associated cancers. However, there are limited data on combination therapy with PARPi and platinum drugs, the mechanism of action of this combination, and the role of BRCA1 or BRCA2 in chemosensitivity. We compared the efficacy of ABT-888 (a PARPi) with that of cisplatin or carboplatin (platinum drugs) alone or in combinations by examining the survival of treated Brca-proficient and -deficient mouse embryonic stem cells. In addition, drug-induced growth inhibition of a BRCA1 and a BRCA2 null cell line were compared with their isogenic BRCA-complemented lines. Although each monotherapy killed or inhibited proliferation of Brca/BRCA-deficient cells, an enhanced effect was observed after treatment with ABT-888 in combination with carboplatin. Moreover, the ABT-888/carboplatin combination delayed tumor growth in Brca2 xenografts. The drugs caused DNA damage and apoptosis. Along with greater PARP activity in Brca/BRCA-deficient cells, these effects correlated with increased chemosensitivity. Our data suggest that ABT-888 and carboplatin combination treatment will be more successful than monotherapy in addressing many BRCA-associated cancers. A randomized phase II trial has recently been initiated to test this hypothesis to assist in the discovery of more effective therapies for patients with BRCA.[3] Purpose: The present study was undertaken to determine the effects of dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of the cancer chemotherapeutic agents carboplatin and gemcitabine. Experimental design: Antitumor activities of carboplatin and gemcitabine with or without DEX pretreatment were determined in six murine-human cancer xenograft models, including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined by using the LS174T, A549, and H1299 models. Results: Although DEX alone showed minimal antitumor activity, DEX pretreatment significantly increased the efficacy of carboplatin, gemcitabine, or a combination of both drugs by 2-4-fold in all xenograft models tested. Without DEX treatment, the tumor exposure to carboplatin, measured by the area under the curve, was markedly lower than normal tissues. However, DEX pretreatment significantly increased tumor carboplatin levels, including 200% increase in area under the curve, 100% increase in maximum concentration, and 160% decrease in clearance. DEX pretreatment similarly increased gemcitabine uptake in tumors. Conclusions: To our knowledge, this is the first report that DEX significantly enhances the antitumor activity of carboplatin and gemcitabine and increases their accumulation in tumors. These results provide a basis for further evaluation of DEX as a chemosensitizer in patients.[4] Aim: The phosphatidylinositol 3-kinase (PI3K)/protein kinase B(AKT)/mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in many types of cancer, including breast cancer. It is recognized that breast cancer cells develop resistance to a variety of standard therapies through the activation of this pathway. We hypothesized that targeting this signaling by the mTOR inhibitor RAD001 may potentiate the cytotoxicity of a conventional chemotherapeutic drug, carboplatin, and enhance the treatment efficacy for breast cancer. Materials and methods: Cell proliferation was measured with 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay; cell apoptosis with enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used for the analysis of cell cycle distribution and mitochondrial membrane function. Gene expression at the protein level was determined by Western blot. Results: MTOR inhibitor RAD001 enhanced the sensitivity of breast cancer cells to carboplatin. RAD001 in combination with carboplatin resulted in synergistic inhibition of cell proliferation and caspase-independent apoptosis in these cells. Moreover, in MCF-7 and BT-474 cells, synergistic effects of this combination on G₂/M cell cycle arrest and regulation of different molecules responsible for cell cycle transition and apoptosis were observed. The p53 pathway was involved in the synergism of RAD001 and carboplatin on breast cancer cell proliferation and apoptosis, since the synergistic effect was demonstrated in all tested breast cancer cell lines with wild-type p53 and the use of p53 inhibitor partially antagonized the effect of RAD001 and carboplatin on p53 and p21 expression, as well as their inhibitory effect on cell proliferation. However, a synergistic effect of the combination of the two drugs on cell proliferation was observed in two p53-mutated cell lines with high AKT expression, suggesting that an alternative mechanism underlying the observed synergism exists. Conclusion: Our results suggest that the combination of RAD001 and carboplatin is a promising treatment approach for breast cancer. On the basis of these results, we have initiated a phase I/II clinical trial with the combination of carboplatin and RAD001 in patients with metastatic breast cancer.[5] |
Solubility Data
| Solubility (In Vitro) |
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| Solubility (In Vivo) |
Note: Carboplatin is generally not recommended to be dissolved in DMSO, as platinum-based drugs are prone to deactivation in DMSO. Additionally, Carboplatin is not stable in solution and should be prepared immediately before use. Solubility in Formulation 1: 10 mg/mL (26.94 mM) in PBS (add these co-solvents sequentially from left to right, and one by one), clear solution; with sonication (<60°C). Solubility in Formulation 2: Water: 14 mg/mL (Please use freshly prepared in vivo formulations for optimal results.) |
| Preparing Stock Solutions | 1 mg | 5 mg | 10 mg | |
| 1 mM | 2.6936 mL | 13.4680 mL | 26.9360 mL | |
| 5 mM | 0.5387 mL | 2.6936 mL | 5.3872 mL | |
| 10 mM | 0.2694 mL | 1.3468 mL | 2.6936 mL |