Originally posted May 22, 2012
I was going to write my #ToxicCarnival post on oxalic acid and rhubarb. Oxalic acid is the molecule that makes rhubarb leaves poisonous. If you ingest it, oxalic acid will bind with all sorts of metals in your body and, in effect, will leach your system of much needed minerals. Of particular note is one of the products of this leaching, calcium oxalate. Calcium oxalate is one of the most abundant molecules found in kidney stones.
That is what I was going to write about.
But, as I sat down to work on it, I got a call from one of my college roommates. It had been a while since we had spoken, and I was excited to have him on the line. But calls like this, out of the blue, usually come with some sort of news.
He told me that the wife of one of our friends had just succumbed to cancer. (For the rest of this post we’ll call them Steve and Nicole.)
Nicole’s is an achingly sad story of an illness, intense resolve, fierce love, determined survival, and ultimately, defeat. She leaves this world a better place. A husband. Two children. Countless friends and loved-ones whose lives she blessed.
The sum-total of Nicole’s story is no different than any other person who dies while suffering from cancer. A beautiful life is lost. The people who benefited form that life mourn. Surely there are details in her struggle that distinguish it from others. And, undoubtedly, her friends and parents and husband and children will tell you why she is special. And they would be absolutely correct.
She was a wonderful woman. She will be fiercely missed.
But what unites each person who suffers is this disease … and the battery of molecules used to treat it.
Truly, every cancer, like every person, is unique. Each individual is going to respond to their cocktail of medication in their own unique way. The trick that chemists, pharmacologists, and physicians set out to perform is to: 1) design molecules that will indiscriminately attack different types of cancer 2) determine the types of people and cancers that respond best to these medicines 3) figure out how best to “package” these molecules so that patients will respond in the best possible way and 4) determine which combination of all of these drugs has the highest potential to cure a unique patient.
I know I am missing details here. And, I know that most of the readers of this blog know this story better than I do.*
But the story arc of cancers and how they are treated are resonating with me now during our larger conversation on toxic chemicals and, importantly, the loss of a friend.
This confluence keeps leading me back to chemicals we use to treat cancer.
Make no mistake about it, these molecules ARE killers.
They are made to be toxic. They are made to destroy tumors. They are made to destroy cells.
The magic of the pharmaceutical enterprise is to find molecules that are better at destroying cancer cells than they are at destroying healthy cells.
I call it magic because I am in awe of the process. Make no mistake about it, this “magic” is carried out by hundreds to thousands of researchers working against a disease that can seem like a moving target. This magic is science at scale.
I thought I’d give a brief overview of just a few of the molecules that we have at our disposal to treat cancer. I’ll discuss the mechanism by which these molecules kill and heal all at the same time.
Cisplatin is a molecule that binds and disrupts DNA. If you imagine DNA as a twisted ladder, cisplatin sneaks in between the slats of the ladder and breaks the rungs apart. Granted, the dosage of cisplatin isn’t high enough to break apart every rung. But, it breaks apart enough rungs that the cell realizes that something is wrong and sets in motion the process of killing itself. This molecule does not discriminate between healthy and diseased cells. For a hypothetical person 5’5″ tall and 136lbs a 50mg/m2 dose (a reasonable amount) translates to a more understandable value 1.34mg/kg (1.34 milligrams given for every kilogram a person weighs). (Calculation Source). Here are some toxicity specs for cisplatin: LD50 (oral): 25.8 mg/kg (rat), 32.7mg/kg (mouse). (Source) (Note: LD50 is the dosage required to kill 50% of test animals). Side effects include: nausea, kidney damage, nerve damage, low blood counts, and others.
Doxorubicin also attacks a cell’s DNA. It works by intercalating between DNA base pairs. (In english: It slips in between the rungs of the ladder). The molecule is bulky enough that, after it intercalates, it prevents the DNA from replicating in cell division, and, thus, keeps the cancer cells from proliferating and stops tumor growth. Given the same hypothetical person as described above: a typical dose might be 1.61 mg/kg. (Source and Calculator) The toxicity specs for doxorubicin are: LD50 (oral): 698 mg/kg. (Source) Overdosage of this drug can cause heart failure. Side effects include: nausea, low blood counts, hair loss, red urine, and others.
Taxol disrupts cellular mitosis by stabilizing the microtubules that form during cell division. Cells that are treated with taxol can never fully divide. This keeps cancer cells from proliferating and tumors from growing. A typical taxol dosage might be 4.68 mg/kg (Source and Calculator). The toxicity specs for taxol are: LD50 (taken by I.V.): 85 mg/kg (rat) and 12 mg/kg (mouse). (Source) Side effects include low blood count, hair loss, joint pain, numbness, nausea, diarrhea, and others.
Cytoxan works by attacking DNA. Again, imagine DNA as a twisted ladder. But now, picture that the ladder is floppy. Cytoxan can stitch the DNA together where it bends. When the cell detects that this is happening, it begins the process of killing itself. A typical cytoxan dosage for our hypothetical patient is 40 mg/kg. (Source) The toxicity specs for cytoxan are: LD50 (oral): 94 mg/kg (rat) and 350 mg/kg (mouse). (Source) Side effects include: nausea, diarrhea, hair loss, lethargy, and others.
Capecitabine is a prodrug, which means that it is converted into the working drug molecules by enzymes within the cancer cell. Capecitabine is broken down into molecules that are used by the cells to take the place of the normal DNA bases in DNA. These modified-DNA are different enough that the cells realize that something is wrong and start to kill themselves. Capeceitabine is taken orally at a dosage of 66.89 mg/kg. (Source and Calculator). The toxicity specs for capecitabine are: LD50 (oral): > 2000 mg/kg (rat). (Source) Side effects include: heart attack, numbness, diarrhea, nausea, anemia, and others.
I bring these drugs, and their properties, up for several reasons.
First: In order to kill the cancer cells, you are going to kill healthy cells and test the limits of your own body’s ability to recuperate. My heart goes out to anyone who is on a chemo regiment. These drug molecules are both good and evil and are neither good nor evil. They serve a specific purpose. It is up to us to understand what purpose they can play and what the collateral damage might be.
This is true for ANY and EVERY molecule that we use in our everyday lives. It is imperative that we understand the risks of exposure to the chemicals that we put in our products. It is imperative that we, as consumers, demand to know how the molecules we come in contact with may affect us. And, although it is reasonable to fear contact with “chemicals”, we need to understand that it is the DOSAGE, not the mere presence, that can lead to adverse effects. We need to be able to shelve our anxiety about the fact that we are exposed to certain chemicals IF we are exposed to levels that are low enough to preclude injury and IF these chemicals don’t accrue in our bodies over time.
Second: The toxicity dosage data that I have shown is for rats and mice. What about humans? Well, unless we want to start testing the human limit for exposure to these molecules, we are out of luck. It is likely that the rat and mouse data are the best that we can expect. Unfortunately these numbers don’t translate perfectly into human reactions to the same molecules. Again, they are a guidepost for what we can expect for humans. As long as the dosage or exposure levels are well below what cause harm/adverse effects, we can be fairly certain that a chemical will not hurt us.
In terms of the cancer pharmaceuticals, we push up to and over the limits of exposure that causes side effects. We all know people who have gone through chemotherapy. All of us have seen, and perhaps even experienced, the ubiquitous hair loss and nausea that goes along with all of these drugs. It is the price that, until better drugs are discovered and approved, must be paid.
At the moment, life seems criminally unfair. Steve and Nicole are two of the kindest and most generous and vibrant people that I know. And I ache for Steve and his loss.
In memory of her, I plan to make a donation to the Breast Cancer Research Foundation. This money will go to support researchers who are looking for new drugs that cure a little more and harm a little less. As a chemist, I don’t know of any more noble or inspiring cause. I hope that you will join me, in some way, in supporting this necessary work.
-mrh
*Please forgive me for my haste in writing this. If there are any medicinal chemists, pharmacologists, synthetic chemists out there who want to add details or stories about the goals and processes of drug development, please feel free to add them in the comment section.