DNA Alkylator

The combination of ABT-888/Carboplatin 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]

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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.[1]

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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]

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Carboplatin (60 mg/kg intraperitoneally) administered as a single agent in A2780 tumor xenografts exhibits a moderate antitumor effect, with day 6 tumor weights (T/C) of 67% and relative tumor volumes of 8.4 versus 11.9 on that day.[1] In comparison to the vehicle group, carboplatin treatment causes a 42% reduction in tumor mass and delays the growth of the tumor in the VC8 (Brca2-deficient) xenografts.[3]

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.

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.[1]

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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.[4]

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Mice: In female athymic NCr nude mice (nu/nu), the A2780 human ovarian cancer cell line is cultivated as a subcutaneous xenograft by injecting 4 × 106 cells into each flank. Six mice per group are randomly assigned to receive treatment with either a control vehicle (43% ethanol, 33% polypropylene glycol, and 24% cremaphor diluted 1:7 with sterile water) days 1-4, 80 mg/kg intraperitonially (17-AAG), 60 mg/kg IP day 0 of carboplatin, or a combination of both (17-AAG, 80 mg/kg IP days 1-4) and Carboplatin, 60 mg/kg IP day 0). Tumor growth is measured three times per week, and volumes are computed using the following verified formula: volume = 4.19 × (a/4 + b/4)3, where a represents the longer diameter and b the shorter. Next, tumor volumes are expressed as a percentage of the volume at treatment initiation, or relative tumor volume.

Effects During Pregnancy and Lactation
◉ Overview of Medication Use During Lactation
Most data suggest that mothers receiving anti-tumor therapy should not breastfeed, especially those using alkylating agents (such as carboplatin). During intermittent treatment, breastfeeding may be safe if the duration is appropriate, but the specific duration is unclear. With repeated chemotherapy cycles, platinum levels in breast milk may increase, but the specific forms of platinum in breast milk and its toxicity are unknown. Breastfeeding infants ingest platinum compounds orally, not intravenously, and the absorption of orally ingested platinum compounds by infants is unclear. Therefore, breastfeeding after carboplatin chemotherapy appears unsafe, and breastfeeding should be discontinued.
Chemotherapy may adversely affect the normal microbiota and chemical composition of breast milk. Women receiving chemotherapy during pregnancy are more likely to experience breastfeeding difficulties.
◉ Effects on Breastfed Infants
No relevant published information was found as of the revision date.
◉ Impact on Lactation and Breast Milk
A telephone follow-up study surveyed 74 women who received chemotherapy for cancer at the same center during the second or third trimester to determine their postpartum breastfeeding success. Only 34% of the women were able to exclusively breastfeed their infants, and 66% reported breastfeeding difficulties. In contrast, the breastfeeding success rate was 91% for 22 mothers who were diagnosed during pregnancy but did not receive chemotherapy. Other statistically significant correlations included: 1. Mothers experiencing breastfeeding difficulties received an average of 5.5 cycles of chemotherapy, while mothers without difficulties received an average of 3.8 cycles; 2. Mothers experiencing breastfeeding difficulties received their first chemotherapy cycle an average of 3.4 weeks earlier. One of the three women who received chemotherapy regimens containing the similar drug cisplatin experienced breastfeeding difficulties.

[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.

Carboplatin may cause developmental toxicity depending on state or federal labeling requirements.
An organoplatinum compound with antitumor activity.
See also: Carboplatin (note moved to).

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Objective: To investigate the interaction between the heat shock protein 90 (HSP90) inhibitor 17-allylamino-17-demethoxygerdromycin (17-AAG) and carboplatin in vitro and in vivo. Experimental Design: The effect of the combination of 17-AAG and carboplatin on the growth inhibition of A2780, SKOV-3, IGROW-1, and HX62 human ovarian cancer cells was investigated in vitro using the MTT assay. The effect of the order of administration of the two drugs on A2780 cells was further investigated using the sulforhodamine B assay. The ability of 17-AAG alone or in combination with carboplatin to deplete HSP90 client proteins was assessed by Western blotting. The concentrations of 17-AAG and carboplatin alone or in combination in tumors in vivo were determined using validated liquid chromatography-UV detection and atomic absorption spectrometry. The growth-inhibiting effects of 17-AAG, carboplatin, and their combination were investigated in the A2780 xenograft tumor model. Results: When A2780 cells were treated with carboplatin followed by 17-AAG, the combined index (CI) of 17-AAG and carboplatin was 0.97 (±0.12 SD) at fu(0.5), indicating an additive effect. Adding carboplatin did not alter the ability of 17-AAG to induce C-RAF, CDK4, and p-AKT depletion or HSP70 expression. There were no significant differences in intratumoral concentrations of 17-AAG and carboplatin between the single-drug and combination-drug groups. On day 6, tumor weight relative to the control group (T/C) was 67% in the carboplatin group, 64% in the 17-AAG group, and 22% in the combination-drug group. Conclusion: Under the specified dosing sequence, 17-AAG and carboplatin have additive growth-inhibiting effects in vitro, and their combination in vivo shows beneficial effects. These findings lay the foundation for evaluating the efficacy of 17-AAG and carboplatin in clinical trials. [1]

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Introduction: Chemotherapy for advanced, well-differentiated carcinoids is characterized by low response rates and short durations of response. This study aimed to evaluate the in vitro activity of novel platinum-based chemotherapy drugs combined with dichloroacetic acid (DCA, an apoptosis sensitizer) against lung cancer carcinoid cell lines. Methods: Three immortalized cell lines (UMC-11, H727, and H835) were exposed to 14 known cytotoxic drugs and novel platinum compounds (such as saxaplatin, JM118, and picoplatin) in combination with DCA, and cell viability was determined using the tetrazolium salt method. Results: Except for the highly resistant UMC-11 cell line, the other carcinoid cell lines (H727 and H835) showed in vitro sensitivity to most chemotherapy drugs. Among the platinum-based drugs, carboplatin and oxaliplatin showed the best efficacy. Compared to single-cell suspensions, H835 cells growing in a multicellular spheroidal form exhibited 2.7–8.7-fold increased resistance to picoplatin, saxaplatin, and their metabolites. DCA (10 mM) inhibited UMC-11 cell growth by 22% and increased the sensitivity of these highly resistant cells to carboplatin, saxaplatin, and JM118 by 1.4–2.4-fold. Conclusion: Highly resistant UMC-11 lung carcinoid cancer cells are sensitive to carboplatin, oxaliplatin, and the saxaplatin metabolite JM118, but multicellular spheroidal growth, as observed in the H835 cell line and lung tumors, appears to significantly enhance chemotherapeutic resistance. The activity of carboplatin and JM118 was significantly and specifically enhanced when combined with the apoptosis-sensitizing agent DCA, which promotes mitochondrial respiration rather than aerobic glycolysis. In conclusion, among novel platinum-based drugs, saxaplatin has the potential to treat lung carcinoid cancers, while DCA can enhance the cytotoxicity of certain platinum-based drugs. [2] Individuals carrying hereditary BRCA1 or BRCA2 mutations have an increased risk of developing breast cancer. The resulting tumors often lack homologous recombination repair, as do some sporadic acquired BRCA-deficient tumors. Monotherapy with platinum-based drugs or poly-PARP inhibitors (PARPi) has shown clinical efficacy in BRCA-related cancers. However, data on PARPi combined with platinum-based drugs, the mechanism of action of this combination therapy, and the role of BRCA1 or BRCA2 in chemosensitivity remain limited. We compared the efficacy of ABT-888 (a PARP inhibitor) with cisplatin or carboplatin (platinum-based drugs) alone or in combination by examining the survival rates of treated BRCA-normal and BRCA-deficient mouse embryonic stem cells. Furthermore, we compared the growth-inhibiting effects of the drugs on BRCA1 and BRCA2-deficient cell lines and their homologous BRCA-complementary cell lines. While each monotherapy killed or inhibited the proliferation of BRCA/BRCA-deficient cells, stronger efficacy was observed with ABT-888 in combination with carboplatin. In addition, the combination of ABT-888 and carboplatin can delay the growth of BRCA2 xenografts. These drugs can cause DNA damage and apoptosis. With the enhancement of PARP activity in BRCA/BRCA-deficient cells, these effects are associated with increased chemosensitivity. Our data suggest that the combination of ABT-888 and carboplatin is more effective than monotherapy in treating a variety of BRCA-related cancers. A randomized phase II trial has recently been initiated to validate this hypothesis in order to help find more effective treatments for BRCA patients. [3]

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Objective: This study aimed to determine the effect of dexamethasone (DEX) pretreatment on the antitumor activity and pharmacokinetics of the anticancer chemotherapy drugs carboplatin and gemcitabine. Experimental Design: The antitumor activities of carboplatin and gemcitabine with and without DEX pretreatment were determined in six mouse-human xenograft models, including colon cancer (LS174T), lung cancer (A549 and H1299), breast cancer (MCF-7 and MDA-MB-468), and glioma (U87-MG). The effects of dexamethasone (DEX) on the plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined using the LS174T, A549, and H1299 models. Results: Although DEX monotherapy exhibited very low antitumor activity, DEX pretreatment significantly improved the efficacy of carboplatin, gemcitabine, or their combination in all tested xenograft models by 2–4 times. Without DEX treatment, tumor exposure to carboplatin (measured by area under the curve) was significantly lower than in normal tissues. However, DEX pretreatment significantly increased the concentration of carboplatin in tumors, including a 200% increase in area under the curve, a 100% increase in maximum concentration, and a 160% decrease in clearance. DEX pretreatment also increased tumor uptake of gemcitabine. Conclusion: To our knowledge, this is the first study to 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 dexamethasone (DEX) as a chemosensitizer in patients. [4]

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Objective: The phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT)/mammalian target of rapamycin (mTOR) signaling pathway is aberrantly activated in a variety of cancers, including breast cancer. Breast cancer cells are known to develop resistance to a variety of standard therapies by activating this pathway. We hypothesized that targeting this signaling pathway with the mTOR inhibitor RAD001 could enhance the cytotoxicity of the conventional chemotherapeutic drug carboplatin and improve the treatment efficacy of breast cancer. Materials and Methods: Cell proliferation was detected using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazol bromide (MTT) assay; apoptosis was detected using enzyme-linked immunosorbent assay (ELISA). Cell cycle distribution and mitochondrial membrane function were analyzed by flow cytometry. Gene expression at the protein level was detected by Western blot. Results: The mTOR inhibitor RAD001 enhanced the sensitivity of breast cancer cells to carboplatin. The combination of RAD001 and carboplatin synergistically inhibited the proliferation of these cells and induced caspase-independent apoptosis. Furthermore, in MCF-7 and BT-474 cells, the synergistic effect of this combination on G₂/M phase cell cycle arrest and the regulation of cell cycle transition and apoptosis-related molecules was observed. The p53 pathway is involved in the synergistic effect of RAD001 and carboplatin on breast cancer cell proliferation and apoptosis, as this synergistic effect was observed in all wild-type p53 breast cancer cell lines tested, while the use of p53 inhibitors partially antagonized the effects of RAD001 and carboplatin on p53 and p21 expression, as well as their inhibitory effect on cell proliferation. However, a synergistic effect on cell proliferation was observed in two p53 mutant cell lines with high AKT expression, suggesting that there may be other mechanisms leading to the observed synergistic effect. Conclusion: Our results suggest that the combination of RAD001 and carboplatin is a promising treatment for breast cancer. Based on these results, we have initiated a phase I/II clinical trial of carboplatin in combination with RAD001 in patients with metastatic breast cancer. [5]

C6H12N2O4PT

371.25

371.044

C, 19.41; H, 3.26; N, 7.55; O, 17.24; Pt, 52.55

41575-94-4

426756

White solid powder

366.4ºCat 760 mmHg

228-230ºC

189.6ºC

0.817

4

6

0

13

177

0

[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]

VSRXQHXAPYXROS-UHFFFAOYSA-N

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

azanide;cyclobutane-1,1-dicarboxylic acid;platinum(2+)

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

2931.90.9051

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.

Room temperature (This product is stable at ambient temperature for a few days during ordinary shipping and time spent in Customs)

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).

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Solubility in Formulation 2: Water: 14 mg/mL

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 (Please use freshly prepared in vivo formulations for optimal results.)