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What is Carboplatin?

Feb 10，2020

Carboplatin is a second-generation platinum compound analog with established activity against a broad spectrum of solid tumors including brain tumors, neuroblastoma, rhabdomyosarcoma, and germ cell tumors. It is commonly used for pediatric cancer and approximately one-third of children with solid tumor are estimated to receive carboplatin at some point during their treatment.[1]

Once carboplatin penetrates the cell membrane, carboplatin is subjected to hydrolysis becoming positively charged. The hydrolyzed product is capable of reacting with any nucleophile, such as the sulfhydryl groups on proteins and nitrogen donor atoms on nucleic acids. Carboplatin connects to the N7 reactive center on purine bases, which elicits DNA injury that blocks replicative machinery and directs cancer cells towards apoptosis. The spectrum of chemical changes induced by carboplatin within DNA is wide, however, the most prominent is the formation of the 1,2-intrastrand [d(GpG)and d(ApG)] adducts of purines. [2]

It has been found that carboplatin may induce DNA damage and cancer cell death also by induction of oxidative stress, particularly the overproduction of mitochondrial reactive oxygen species (ROS) and by decreasing the pool of intracellular antioxidants, e.g. reduced glutathione (GSH). Among signaling molecules and pathways activated in response to cisplatin and involved in the drug-related cytotoxicity, the most important include: p53, extracellular-signal-regulated kinase (ERK), and c-JunN-terminal kinase (JNK). Although carboplatin has dose-limiting toxicities such as myelosuppression, there are relatively few nonhematological toxicities. It is thus an important agent to be used widely in high-dose settings such as high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). [3]

Carboplatin is largely cleared by the kidneys at a rate comparable to the glomerular filtration rate (GFR). Following a dose of carboplatin, approximately 60–80% is excreted in the urine within the first 24 h. Consequently, the PK of carboplatin is largely determined by renal functions of the patients.

In all, Carboplatin remains a commonly-used chemotherapeutic agent for treatment of various malignancies, with its dose-limiting toxicity being thrombocytopenia.[4]

References

1.Gaynon PS. Carboplatin in pediatric malignancies. Semin Oncol. 1994, 21:65–76.

2.Veal GJ, Errington J, Tilby MJ, Pearson AD, Foot AB, McDowell H, et al. Adaptive dosing and platinum-DNA adduct formation in children receiving high-dose carboplatin for the treatment of solid tumours. Br J Cancer. 2007, 96:725–31.

3.Calvert AH, Newell DR, Gumbrell LA, O’Reilly S, Burnell M, Boxall FE, et al. Carboplatin dosage: prospective evaluation of a simple formula based on renal function. J Clin Oncol. 1989, 7:1748–56.

4.https://www.drugbank.ca/drugs/DB00958

5.https://en.wikipedia.org/wiki/Carboplatin