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Cisplatin

Cisplatin or cis-diamminedichloroplatinum(II) (CDDP) is a platinum-based chemotherapy drug used to treat various types of cancers, including sarcomas, some carcinomas (e.g. small cell lung cancer and ovarian cancer), lymphomas and germ cell tumors. It was the first member of its class, which now also includes carboplatin and oxaliplatin. more...

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Pharmacology

Mode of action

Cisplatin acts by crosslinking DNA in various different ways, making it impossible for rapidly dividing cells to duplicate their DNA for mitosis. The damaged DNA sets off DNA repair mechanisms, which activate apoptosis when repair proves impossible. The trans isomer does not have this pharmacological effect.

Most notable among the DNA changes are the intrastrand GpG adducts which form nearly 90% of the adducts. Other adducts include inter-strand crosslinks and nonfunctional adducts that have been postulated to contribute to its activity. Interaction with cellular proteins has also been advanced as a mechanism of interfering with mitosis, although this is probably not its main action.

Side effects

Cisplatin has a number of side-effects that can limit its use:

  • Nephrotoxicity (kidney damage) is a major concern when cisplatin is prescribed as a chemotherapy agent. The dose therefore has to be tailored to the patient's creatinine clearance (a measure of renal function), and adequate hydration and diuresis is used to prevent renal damage.
  • Neurotoxicity (nerve damage) can be anticipated by performing nerve conduction studies before and after treatment.
  • Nausea and vomiting. Cisplatin is one of the most emetogenic chemotherapy agents, but this is managed with prophylactic antiemetics (e.g. ondansetron, granisetron, etc.) in combination with corticosteroids.
  • Ototoxicity (hearing loss)
  • Hair loss.

History

As a compound cisplatin was first described by M. Peyrone in 1845. The structure was elucidated by Alfred Werner in 1893. It was rediscovered in the 1960s by Rosenberg et al, who discovered that electrolysis products from a platinum electrode inhibited mitosis in Escherichia coli (E. coli) bacteria. The bacteria grow to 300 times their normal length but cell division fails.

In the 1970s, a series of experiments were conducted at Michigan State University to test the effects the cis-diamminedichloroplatinum(II), along with other platinum coordination complexes, on sarcomas artificially implanted in rats. This study found that cis-diamminedichloroplatinum(II) was the most effective out of this group, which started the medicinal career of cisplatin.

Approved for clinical use by the American Food and Drug Administration (FDA) in 1978, it revolutionized the treatment of certain cancers. Detailed studies on its molecular mechanism of action, using a variety of spectrocopic methods including X-ray, NMR and other physico-chemical methods, revealed its ability to form irreversible crosslinks with bases in DNA.

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Multidisciplinary treatment for advanced invasive thymoma with cisplatin, doxorubicin, and methylprednisolone
From CHEST, 10/1/05 by Kohei Yokoi

PURPOSE: Advanced thymomas (stage III with great vessel involvement and Stage IV) are not usually manageable by surgical resection and radiotherapy, and effectiveness of multimodality therapy including chemotherapy has been recently reported. However, the optimal treatment strategy has not been determined. We reviewed our experience with a multidisciplinary approach and evaluated the chemotherapy in the treatment of invasive thymoma.

METHODS: Seventeen patients were treated with multimodality therapy consisted of chemotherapy, surgery, and/or radiotherapy. Four patients had stage III disease with superior vena cava invasion, 9 had stage IVa disease, and 4 had stage IVb disease. The chemotherapy regimen consisted of cisplatin (20 mg/m2/day on days 1-4), doxorubicin (40 mg/m2 on day 1), and methylprednisolone (1,000 mg/day on days 1-4 and 500 mg/day on days 5, 6) (CAMP). Chemotherapy was administered in a neoadjuvant setting to the 14 patients and in an adjuvant setting to the remaining 3patients with stage IVa disease. Surgical resection was intended in all patients. After those treatments, chemotherapy and/or radiation therapy were performed.

RESULTS: All but one of the 14 patients with induction chemotherapy had responded to the CAMP therapy, and the response rate (CR: 1, PR: 13) was 92.8%. One patient with MG, PRCA, and hypogammaglobulinemia died during the chemotherapy. Eight patients of them had a CR after surgical resection and chemoradiotherapy. All three patients treated with surgical resection followed by chemotherapy with or without radiotherapy achieved also a CR. Recurrences occurred in 6 patients, but 4 of them are now alive after re-treatment. The 10-year survival of all the patients was 80.7%, and 11 patients with a complete remission after the multidisciplinary treatment are all alive 9 to 193 months after initiation of the therapy.

CONCLUSION: The CAMP therapy was highly effective to invasive thymomas. The multidisciplinary treatment containing this chemotherapy is considered a justifiable treatment strategy for patients with advanced thymoma.

CLINICAL IMPLICATIONS: The high efficacy of chemotherapy will contribute to improve the outcomes of patients with unresectable invasive thymoma.

DISCLOSURE: Kohei Yokoi, None.

Kohei Yokoi MD * Haruhisa Matsuguma MD Rie Nakahara MD Tetsuro Kondo MD Yukari Kamiyama MD Kiyoshi Mori MD Nagoya Graduate School of Medicine, Nagoya, Japan

COPYRIGHT 2005 American College of Chest Physicians
COPYRIGHT 2005 Gale Group

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