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
 * 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

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