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Published: Monday, 2/19/2007

Rats Redux: Dichloroacetate

This weekend I wrote about the drug dichloroacetate in the entry Of Rats & Men.

If you read that, skip this refresher paragraph: In that entry I argued that, while DCA has seen promising results against cancer in cell line investigations and in rats injected with cancer cells, it is not ready for human use, despite a growing frenzy for its release. Unfortunately, experimental drugs do occasionally cure cancer in rats and mice, but then fail to do the same for humans. We are not rats.

One reader, Greg Lipps, a herpetologist, responded with this observation. Before you read it, you should know that the term LD 50 means median lethal dose, that is, a dose of a compound that kills half of a tested population:

"Several years ago, I saw a presentation about human snake envenomation. The speaker repeatedly told the audience, 'Mice are not miniature people.' His proof came from the various lists of LD 50's for snake venom that had been calculated using (you guessed it) mice. The problem was that some of the [venoms] at the top of the list (very low LD 50's -- very toxic...to mice), didn't appear to cause fatal envenomations in humans, while some of the snake [venoms] that the mice found to be less toxic were very efficient people killers. Mice are not miniature people."

Interesting stuff about the snake venom, Greg. I didn't know that. That's an impressive demonstration of why the outcome of animal studies are not predictive for humans, but instead just suggestive.

My second response to the entry on dichloroacetate was from Dave. He calls himself Tall Dave, actually. He is also one of the people who prompted me to write about DCA in the first place. Dave is a scientist. He is also between chemo treatments for stage IV cancer:

"I certainly see your point and the 'scientist' side of

me agrees 100%. But when you sit on this side of the 'C' diagnosis, you

know it's loose in your body, and you're relatively young (52), the shade of

your glasses tends to change. As I've said all along, this is a risk/reward

issue for me and one I'd like to explore.

Dave, you have me thinking.

A couple of years ago, I followed a group of folks through a Phase 1 trial of a cancer drug called H-11 and wrote a series called Working on a Cure.

As in all Phase 1 trials, the purpose was to test for safety of this new drug, not its efficacy. Drug investigations don't look to see if the drug actually works until Phase 2 and 3. The patients in the H-11 trial knew that, but they couldn't help themselves. Every one of them were hoping, if not for a cure, than at least for a little more time. All of them had end-stage cancers. All had been through numerous cancer treatments already, and all had suffered multiple recurrences.

I should add that H-11 worked well in animal studies.

Sadly, H-11 did nothing for these patients. All of them died. But in the months that followed the trial, when we knew H-11 wouldn't save them, I watched them hope and cope.

My stories focused mostly on two of the patients, Pat Krzeminski and Cissi Jackson, but there was a third patient I never wrote about who I identified with very closely. Her name was Karen Creque. I had to cut her from my story for the simple reason that she underwent her treatment before Pat and Cissi, and I couldn't weave her tale into their narrative. It was just too awkward.

Pat and Cissi were larger than life in their way and I loved telling their stories. Karen was a different kind of patient. She was the realist, the grit-your-teeth pragmatist. She never used denial to ease her way, but she didn't give up hope, either. She told me when I met her that she expected to die from ovarian cancer, that one day the chemo wouldn't work, but she wanted to buy time. Even after H-11 failed, she regularly checked the websites listing new cancer drug trials. (The National Cancer Institute clinical trials page, and the American Cancer Society clinical trials page,

are good starting points to search for trials.)

And here's the real tragedy: She didn't qualify for any of them. Phase 1 studies, the studies for safety, not for efficacy, are the only ones that will take end-stage patients. If you want to prove your drug works in a Phase 2 or Phase 3 study, you don't give it to the very sickest people, the people with the least hope of recovery. You give it to people who haven't rounded that corner yet.

Sometimes, after talking to Karen, I'd look at the cancer trial websites and try to find something she might have missed. I never did.

So, OK, Tall Dave, I still can't change my mind about releasing animal-tested drugs without human trials, but your story, and my memory of Karen and those others, reminds me how imperfect our testing system is.

Should there be some sort of compassionate use standard? Should there be a way to broaden the use of experimental drugs in a controlled setting? Maybe. Probably.

I was astonished to learn a few years ago that the treatment of cancer in children relies heavily upon experimental drugs. Children are routinely put into experimental protocols, testing the best known therapy against the next promising drug. And look at children's cancer survival rates: This is one of the bright spots in the recent history of cancer treatment. Maybe this says something about how the treatment of adult cancers could be modified. I'm afraid I'm not knowledgeable enough to know what the barriers are, or even what the issues are, but now that we're talking about it, I feel compelled to take a look. I'm going to make some calls. We'll be talking about this again.

And keep writing, folks. I need to hear from you.



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