Probably once a week I get an offer for a platinum credit card. My wedding ring is made of platinum. I have at least one or two albums in my living room that at one point went platinum.
Over the last 450 years, platinum has become a symbol of prestige, wealth and success. Ironically, the Spanish conquistadors, the first Europeans to know of its existence, thought platinum was a nuisance, an impurity they couldn’t separate from the gold they sought. They called it platina, or little silver.
When it came to the nuisance factor, though, the conquistadors couldn’t have been more wrong. Plaitnum’s chemical properties gave us the catalytic converter. It’s rarity (it’s abundance in the earth’s crust hovers around 5 parts per billion) has made it one of the most valuable metals mined (it’s NASDAQ market price was a little under $1,600 per ounce at the time of writing, hence the fiscal cliff-era idea of minting a platinum trillion dollar coin). The physical prototypes of the meter and the kilogram are made from a platinum-iridium alloy.
And about 50 years ago, platinum became the basis of one of the most important anticancer drugs available, cisplatin.
It’s electric, or at least it seemed to be
Cisplatin was first described in the 1840s by an M. Peyrone (which is why it used to go by the name “Peyrone’s salt”), but it’s medical potential wasn’t suspected for about 120 years.
It’s actually one of the great stories of serenidpity in drug discovery. The story goes (and this is to the best of my knowledge – anyone out there, feel free to correct me!) that three scientists at Michigan State University — Rosenberg, Van Camp, and Krigas — set out to see whether electrical currents could be antibiotic. And at first pass it looked like their experiments worked: When they applied a current to a liquid culture of E. coli, the bacteria stopped dividing, instead growing into long filaments 300 times their normal length.
But the electricity wasn’t the whole answer. In 1965, the trio reported in Nature that what actually kept the E. coli from dividing were compounds formed by ions shed from the platinum electrodes they used to generate the current. And in 1970, when Rosenberg and Van Camp found that one of these platinum compounds could shrink soft tissue tumors (called sarcomas) in rats, cisplatin was born.
Building bridges — in DNA
Cisplatin — which also goes by the roll-off-the-tongue names of (SP-4-2)-diamminedichloridoplatinum and cis-diamminedichloroplatinum(II) — earned its first FDA approval in 1978 for testicular and ovarian cancers. Since then, it’s been tested in and approved for a variety of cancers, and is almost single handedly repsonsible for raising the cure rate for testicular cancers from 10 percent to more than 85 percent (making it the right thing for Lance Armstrong to have doped).
But how does it work? To answer that, you need to know cisplatin’s structure:
The Pt in the middle, that’s the platinum. The rest is two atoms of chlorine (the same chlorine that’s in bleach and table salt) and two molecules of ammonia.
Chlorine likes water, a lot. Way more than it likes platinum. So it’s pretty easy for water (and a cell’s nucleus is chock full of water) to grab one of those chorine atoms away from the drug.
Platinum, on the other hand, likes DNA. In particular, it really likes one of the four bases of DNA, called guanine. So when water knocks off a chlorine atom, that gives the platinum an opportunity to grab onto a guanine base.
The process then repeats. Water knocks off cisplatin’s remaining chlorine, opening up another spot for the platinum to attach itself to another guanine, usually on another strand of DNA.
What the cell then ends up with is a platinum atom that “crosslinks” two strands of DNA together.
And cells don’t like crosslinked DNA. They see it as a kind of genetic damage, and try to repair it. If it can’t be repaired (and in cancer cells a lot of the DNA repair machinery is broken anyway), the cell kills itself through a programmed cellular suicide process called apoptosis.
Looking at the future of platinums
Because cisplatin has been so successful, the chemistry of “little silver” is big business in the pharmaceutical world. Over the years, cisplatin is spawned several other platinum-based drugs like carboplatin and oxaliplatin.
Ideally, chemists would love to develop a drug address cisplatin’s shortcomings, like the toxicity (it’s a pretty toxic drug…after all, it can’t really tell the difference between cancer cells and healthy ones), the fact that it only really works when given as an IV (oral drugs are the way to go), and avoid drug resistance.
But in the end, they also want to maintain its potency against tumors, thereby keeping the promise of platinum therapy alive for thousands more cancer patients in the future.