User:Benjah-bmm27/degree/4/PGP

Metals in Therapy and Diagnosis

Content

• Despite the title, this course is all about platinum-based chemotherapy drugs — there's no diagnosis
• Cisplatin (and oxaliplatin) is a blockbuster drug, with sales of more than £1bn a year

Books

• Medicinal Inorganic Chemistry (2005) S. J. Lippard
• Metallotherapeutic drugs and metal-based diagnostic agents (2005) E. R. T. Tiekink

History

• Not examinable
• See Cisplatin#History
• 1844 Peyrone was the first to describe cis-PtCl₂(NH₃)₂
• 1894 Werner discovered PtX₂L₂ compounds exist as several isomers, therefore Pt is not tetrahedral like carbon
• 1964–6 Pt electrodes affect bacterial growth
  • accidental discovery while investigating the effect of electricity on bacterial growth
  • NH₄Cl background electrolyte reacted with Pt electrode, forming tiny quantities of cisplatin
  • to be continued

Drugs discussed

• Cisplatin
• Carboplatin
• Nedaplatin
• Satraplatin
• Picoplatin
• Oxaliplatin
• Aroplatin

• 
  cisplatin
• 
  carboplatin
• 
  nedaplatin
• 
  satraplatin
• 
  picoplatin
• 
  oxaliplatin

Drugs not mentioned but which are related

• Triplatin tetranitrate
• Lipoplatin

Literature references in the notes

1. Lippard, JACS, (1988) 110, 7368
2. Lippard, Nature (1995) 377, 649
3. Lippard, Nature (1999) 399, 708
4. Lippard et al, J. Am. Chem. Soc. (1990) 112, 6860
5. Kelland, Platinum Metal Rev. (1992) 36, 178
6. Kelland, Nature Rev. Cancer (2007) 7, 573
7. Aller et al., Proc. Natl. Acad. Sci. (2009) 106, 4237

Structural consequences of Pt binding to DNA

• Jmol models from crystal structures
  • Lippard, JACS, (1988) 110, 7368
  • Lippard, Nature (1995) 377, 649

Treatment of side effects

• Three approaches:
  • Prevent formation of or rescue Pt from complexes with proteins
  • Induce metallothionein (MT) production in the kidneys
  • Develop a better Pt drug

• 1. First approach: rescuing Pt from proteins
  • RSH and RS⁻ groups on proteins complex Pt, but can be prevented from doing so by a high chloride concentration
    • Administer Pt therapy with a saline drip for dramatic reduction in nephrotoxicity
  • Reverse protein RS–Pt complexes with "rescue agents", administered 3-4 hours after Pt
    • Dithiocarbamates like sodium diethyldithiocarbamate form very strong 4-membered chelates with Pt
    • The hydroxyethyl variant is more hydrophilic but more expensive
    • These rescue agents displace Pt from proteins but do not affect Pt-DNA complexes

• 2. Second approach: induce renal MT production
  • Non-toxic Na₂S₂O₇ or bismuth salts trick the kidneys into producing more MT
  • They recognise Bi as a heavy metal, but it is not toxic unlike Pt, Hg, etc.

• 3. Third approach: better Pt drug
  • Second generation drugs, including carboplatin, nedaplatin, satraplatin and oxaliplatin
  • Carboplatin has low nephro-, neuro- and ototoxicity, outpatient treatment
  • Disadvantages: need 4x dose, 10x cost, and not active against cisplatin-resistant cancer cells
  • Carboplatin is not a pro-drug for cisplatin - reacts with DNA directly