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Platinum containing medications

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Platinum containing medications

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Platinum containing medications

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(drug) is a medication that detoxifies reactive metabolites and scavenges free radicals, and can therefore be used to prevent the nephrotoxicity of cisplatin and carboplatin.

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A 25-year-old man comes to the office because of difficulty hearing. He is a professional cyclist, and a month ago he came to the office because of pain in the groin for a month. He said the pain was constant and has a "dragging" quality. Examination showed that he had an enlarged left testicle, with a firm, solid, mass patient undergoes inguinal orchiectomy, and histopathology shows that he had testicular cancer. He then underwent chemotherapy for treatment. Which of the following chemotherapeutic agents is most likely responsible for this difficulty in hearing?

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Transcript

Platinum containing agents, informally called platins, are a class of medications that are used to treat cancer.

They disrupt the structure of DNA by acting on consecutive guanine bases within a strand of DNA and can affect all phases of the cell cycle.

Okay, now the cell cycle refers to the events that somatic cells, which includes all of the cells in our bodies except the reproductive cells, go through from the moment they’re formed until the moment they divide into two identical daughter cells.

This cycle varies in length depending on the type of cell.

For rapidly dividing cells, like skin cells, it takes less than a day, whereas for other cells, like liver cells, the cell cycle can last years.

Now, the cell cycle can be divided in two phases: interphase and mitosis.

Interphase comprises of the G1 phase, during which the cell grows and performs its cell functions, the S phase, during which DNA is replicated, and the G2 phase, during which the cell grows again before entering mitosis.

Mitosis can be broken down into prophase, metaphase, anaphase, and telophase, during which the replicated DNA divides equally for the two daughter cells, and ends with cytokinesis, which is when the cell membrane actually divides to form the two new cells.

There’s also a G0 phase which is an extended G1 phase, where the cell is resting and not actively preparing to divide.

Alright, now imagine a cancer cell.

This cell is going through the phases of the cell cycle without regulation, and its DNA also replicates more frequently, with less error-correcting than healthy cells.

Therefore, it’s more sensitive to DNA damage.

Here’s a DNA base, guanine.

Platinum containing agents attach at the number 7 nitrogen atom of two adjacent guanines on the same strand of DNA leading to the formation of cross-bridges, or intra-strand cross-linking of the DNA.

The resultant cross-linking inhibits DNA repair and prevents DNA from being separated for replication, eventually leading to cell death.

Platins are cell cycle-nonspecific agents, meaning they act on tumor cells during all phases of the cell cycle, including the resting G0 phase.

Platins are sometimes described as ‘alkylating-like’ agents as they act like DNA alkylating medications, although they do not have an alkyl group.

Okay, platinum containing agents include cisplatin, carboplatin, and oxaliplatin, which are all administered intravenously and eliminated through the kidneys.

As their names imply, they are coordination complexes of platinum, meaning they consist of a central atom of platinum and a surrounding array of bound molecules, or ions, that are called ligands.

Cisplatin has revolutionized the treatment of solid tumors.

Today, cisplatin and carboplatin are used to treat a variety of solid tumors including testicular, bladder, ovarian, cervical, and lung carcinomas.

They are also used in the treatment of osteosarcoma, which is a common malignant bone tumor in children and teens, which arises from osteoblasts.

Oxaliplatin is used to treat solid tumors including advanced colon cancer, hepatobiliary, pancreatic and ovarian carcinomas.

It is also used in the treatment of lymphomas.

Alright, moving on to the side effects.

Platins can cause gastrointestinal disturbances, including very severe nausea and vomiting, which can be prevented by the use of ondansetron.

It’s also seriously nephrotoxic, which is the main dose-limiting side effect.

We can prevent nephrotoxicity with adequate hydration; diuresis using mannitol, an osmotic diuretic; or saline, to prevent the medications from building up in the kidneys.

Sources
  1. "Katzung & Trevor's Pharmacology Examination and Board Review,12th Edition" McGraw-Hill Education / Medical (2018)
  2. "Rang and Dale's Pharmacology" Elsevier (2019)
  3. "Goodman and Gilman's The Pharmacological Basis of Therapeutics, 13th Edition" McGraw-Hill Education / Medical (2017)
  4. "Nomograms" D. Nicoll , C. Mark Lu, S.J. McPhee (Eds.), Guide to Diagnostic Tests, 7e. McGraw-Hill (2017)
  5. "Overview of hemostasis" J.C. Aster, H. Bunn (Eds.), Pathophysiology of Blood Disorders, 2e. McGraw-Hill. (2016)
  6. "Pembrolizumab in the treatment of locally advanced or metastatic urothelial carcinoma: clinical trial evidence and experience" Therapeutic Advances in Urology (2019)
  7. "Efficacy and safety of cisplatin for the management of adult patients with oral cancer" Medicine (2019)
  8. "Platinum Salts in Patients with Breast Cancer: A Focus on Predictive Factors" International Journal of Molecular Sciences (2019)