Platinum-based antineoplastic explained

Platinum-based antineoplastic drugs (informally called platins) are chemotherapeutic agents used to treat cancer. Their active moieties are coordination complexes of platinum. These drugs are used to treat almost half of people receiving chemotherapy for cancer. In this form of chemotherapy, commonly used drugs include cisplatin, oxaliplatin, and carboplatin, but several have been proposed or are under development. Addition of platinum-based chemotherapy drugs to chemoradiation in women with early cervical cancer seems to improve survival and reduce risk of recurrence.[1]

In total, these drugs can cause a combination of more than 40 specific side effects which include neurotoxicity, which is manifested by peripheral neuropathies including polyneuropathy.[2]

Mechanism of action

As studied mainly on cisplatin, but presumably for other members as well, platinum-based antineoplastic agents cause crosslinking of DNA as monoadduct, interstrand crosslinks, intrastrand crosslinks or DNA protein crosslinks. Mostly they act on the adjacent N-7 position of guanine, forming a 1, 2 intrastrand crosslink.[3] [4] The resultant crosslinking inhibits DNA repair and/or DNA synthesis. This mechanism leads to specific patterns of damage in DNA, which can kill cancer cells but can also increase the risk of secondary tumors developing.[5]

Platinum-based antineoplastic agents are sometimes described as "alkylating-like" due to similar effects as alkylating antineoplastic agents, although they do not have an alkyl group.[6]

Examples

Strategies for improving platinum-based anticancer drugs usually involve changes in the neutral spectator ligands, changes in the nature of the anions (halides vs various carboxylates), or changes in the oxidation state of the metal (Pt(II) vs Pt(IV)). Nanotechnology has been explored to deliver platinum more efficiently in the case of lipoplatin, which is introduced into the tumor sites thereby reducing the chance of toxicity.[7]

Cisplatin was the first to be developed.[8] Cisplatin is particularly effective against testicular cancer; the cure rate was improved from 10% to 85%.[9] Similarly, the addition of cisplatin to adjuvant chemotherapy led to a marked increase in disease-free survival rates for patients with medulloblastoma - again, up to around 85%. [10] This application of cisplatin was developed by pediatric oncologist Roger Packer in the early 1980s. [11]

Notes and References

  1. Falcetta. FS. Medeiros. LR. Edelweiss. MI. Pohlmann. PR. Stein. AT. Rosa. DD. Adjuvant platinum-based chemotherapy for early stage cervical cancer.. The Cochrane Database of Systematic Reviews. 22 November 2016. 11. 11 . CD005342. 27873308. 10.1002/14651858.CD005342.pub4. 4164460.
  2. Oun R, Moussa YE, Wheate NJ . 2018 . The side effects of platinum-based chemotherapy drugs: a review for chemists . Dalton Transactions . 47 . 19 . 6645–6653 . 10.1039/c8dt00838h. 29632935 .
  3. Poklar N, Pilch DS, Lippard SJ, Redding EA, Dunham SU, Breslauer KJ . Influence of cisplatin intrastrand crosslinking on the conformation, thermal stability, and energetics of a 20-mer DNA duplex . Proc. Natl. Acad. Sci. U.S.A. . 93 . 15 . 7606–11 . July 1996 . 8755522 . 38793 . 10.1073/pnas.93.15.7606. 1996PNAS...93.7606P . free .
  4. Rudd GN, Hartley JA, Souhami RL . Persistence of cisplatin-induced DNA interstrand crosslinking in peripheral blood mononuclear cells from elderly and young individuals . Cancer Chemother. Pharmacol. . 35 . 4 . 323–6 . 1995 . 7828275 . 10.1007/BF00689452. 24036376 .
  5. Steele . Christopher D . Pillay . Nischalan . Alexandrov . Ludmil B . An overview of mutational and copy number signatures in human cancer . The Journal of Pathology . July 2022 . 257 . 4 . 454–465 . 10.1002/path.5912 . 35420163 . 9324981 . 0022-3417.
  6. Cruet-Hennequart S, Glynn MT, Murillo LS, Coyne S, Carty MP . Enhanced DNA-PK-mediated RPA2 hyperphosphorylation in DNA polymerase eta-deficient human cells treated with cisplatin and oxaliplatin . DNA Repair . 7 . 4 . 582–96 . April 2008 . 18289945 . 10.1016/j.dnarep.2007.12.012 .
  7. Johnstone. Timothy C.. Suntharalingam. Kogularamanan. Lippard. Stephen J.. The Next Generation of Platinum Drugs: Targeted Pt(II) Agents, Nanoparticle Delivery, and Pt(IV) Prodrugs. Chemical Reviews. 116. 5. 2016. 3436–3486. 0009-2665. 10.1021/acs.chemrev.5b00597. 26865551. 4792284.
  8. Kelland . L. . The resurgence of platinum-based cancer chemotherapy . 10.1038/nrc2167 . Nature Reviews Cancer . 7 . 8 . 573–584 . 2007 . 17625587. 205468214 .
  9. Einhorn LH. . Treatment of testicular cancer: a new and improved model . J. Clin. Oncol. . 1 November 1990. 8 . 11 . 1777–81 . 1700077. 10.1200/JCO.1990.8.11.1777 .
  10. Packer, R.. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. . Journal of Neurosurgery . 1994 . 81 . 5 . 690–698. 10.3171/jns.1994.81.5.0690 . 7931615 .
  11. Packer, R.. Outcome for children with medulloblastoma treated with radiation and cisplatin, CCNU, and vincristine chemotherapy. . Journal of Neurosurgery . 1994 . 81 . 5 . 690–698. 10.3171/jns.1994.81.5.0690 . 7931615 .

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