Monday, September 19, 2016

ScienceDay! Chemotherapy

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Originally published on June 4th,  2014

Cancers has been around for a long long time. And it seems like everyday somebody is trying to raise money for research for one cancer type or another. So it can be hard to remember that back in the near past of the '60s "talk of curing cancer with drugs was not considered compatible with sanity." In 1960 there was no medical oncology as a clinical specialty. And even at the National Cancer Institute (NCI) the leukemia service, which did use drugs to treat their patients, was referred to as the "butcher shop" during rounds1.

So how did we go from the proverbial meat wagon - as my father calls the ambulance - to the world of amazing cocktails of drugs and complicated regiments that help many patients find cures, and many more extend their life expectancy through long remissions? To find out, we need to go way back. A good bit farther back than the groovy '60s.

The first accounts, or rather, the earliest surviving accounts of cancer that we are aware of, come from Egypt some 5000 years ago. Two papyri, both named for their very white 'discoverers,' include descriptions of cancer. (As one papyrus was purchased at an antiquities dealer, and never fully translated in the new owner's lifetime, it is hard to call it a real discovery.) Still, the papyri detail hundreds of diseases, drugs, treatments and case histories, including many types of cancers. The treatments involved surgery and cautery with an aptly named "fire drill.1" Needless to say, I'm glad I was born more than a few centuries later.

Hippocrates, the one with the oath, decided that the cause of cancer was the excess of black bile. While he was technically incorrect, and well, just plain incorrect, he did replace the prevailing thought of the day which was cancer was due to retribution for sin. Either way, the treatment didn't change much. Standard practice of care mainly involved surgery and cautery, but also included that delightful cure-all, bloodletting. Yet, not everything from these early days was completely unfounded. Dioscorides, a Greek pharmacologist and botanist made a drug from a crocus plant to treat tumors. The same plant was restudied in 1938 and through a long process many drugs were found that could interfere with cell division. Dioscorides also listed other plants of the genus Vinca that he thought might have cancer-treating powers. And from modern research on some of these, we now have vincristine (which I took as part of my treatment) and other useful drugs1.

As a side note, Hippocrates, gave us the name 'cancer.' Carcinos, in Greek, means crabs. Breast tumors can have long projections that to Hippocrates looked like crab legs. Translating his Greek into Latin, you derive 'cancer.' And that took. All sorts of derivatives started showing, including ‘carcinoma’, which arrived in the 2nd century AD1.

Some years later, (some 1,000) the first hospital for cancer care was founded in Rheims France. Though, at the time it was thought that cancer was contagious. And since the treatment hadn't advanced much past the Egyptian's 'fire drill' people were understandably terrified of catching it. The hospital was run out of town. It was another hundred years before the UK set up their own hospital1.

One of the biggest turning points in drug treatment for cancer came from one of the worst episodes in modern human history. In 1899, at the Hague Convention, the world players agreed to outlaw the use of poison gasses in war. Yet in the second battle of Ypres, the Germans released 168 tons of chlorine gas. Soon, a worse gas, Mustard Sulfur gas, replaced the chlorine. Soon both sides were deploying and drowning in the deadly effects1.

Autopsies of those that had died showed a marked reduction in lymph and bone marrow tissue. Research on mustard gas continued during WWII. Some of that research was done at Yale. Alfred Gilmand and Louis Goodman were two pharmacologists at Yale. They developed a technique to transplant lymphoid tumors into mice. Using these mice, they could test drugs and gasses that might reduce the tumor2. Using nitrogen-mustard (just like Mustard Sulfur, but with a nitrogen atom where the sulfur atom had been), a less toxic, but still potent form of the gas they were able to reduce a lymph tumor in the mouse1, 2. With this information in hand, they found their colleague, Gustaf Lindskog, who had a patient with non-Hodgkin’s lymphoma. The tumor was constricting the patient's airway. Some how Gilmand and Goodman convinced their colleague to treat his patient with this drug from their mouse trial. Clearly, it was a different time. Yet it worked, reducing the size of the tumor. Sadly, the reduction was only temporary. But, at least, this showed that it could be done2.

The going wasn't easy. Paul Ehrlich, one of the first to use the term 'chemotherapy' used arsenic derivatives to treat syphilis. But he also dabbled in cancer treatment. As a testament to the difficulty, over the door to the cancer part of the lab was a sign reading 'give up all hope oh ye who enter.2' Then again, perhaps Ehrlich had sarcastic post-docs. I should get a banner over my bay.

Most of the work was done in just a few places. The largest player during the post-war period was Sloan Kettering Institute. Though much work was done in Boston, London, and Birmingham (Alabama). Still, as mentioned before, there was a lot of resistance. Often it was hard to know if those early drugs, and treatment regiments, did more harm than good. Most often the benefits were temporary. There was still little hope2

The next big improvement came when researchers realized that one would need to kill every cell of a cancer to cure it.  Research showed that a single tumor cell transplanted into a mouse was sufficient to kill the mouse. Higher doses, and careful regiments would be needed if all cells were to be killed2, 3. More and more drugs were being discovered and soon doctors and scientists wanted to try combinations of drugs. In 1960 Hodgkin’s lymphoma was always fatal with treatment of only one drug. A research protocol for treatment was designed which combine nitrogen mustard, vincristine, methotrexate and prednisone (I also took prednisone!) which was named "MOMP." Amazingly, the NIH didn't want to support the research, as it was too much of a departure from established protocols. Fortunately a little politicking from influential people allowed the program to go forward. Almost overnight the remission rate went from 0 to 80%. Today, Hodgkin's is curable in 90% of cases2.

Soon after this advance, the field of medical oncology was officially established (in 1973). Progress continued. In 1975 they were able to cure, for the first time, diffuse large b-cell lymphoma with a collection of drugs known as CMOPP2. The 'C' stands for cyclophopamide - which was in my treatment cocktail as well. This work was done by Joseph Bertino also at Yale university3.

Improvements continued. In the 1990s advances in basic cell biology, development, biochemistry, and biophysics led to an explosion of knowledge about the proteins and pathways that regulate healthy biology and cancerous growth. And the research turned to find more targeted drugs and methods of treatments. Scientists turned to monoclonal antibodies (MAbs). MAbs bind to one specific protein. You can make MAbs targeted to almost any protein. The first MAb used in combination with traditional chemotherapy was Rituximab. It binds to CD-20 which is a protein found on the outside of b-cells (part of our immune system). The b-cells bound by the MAb are then destroyed2. (This was also part of my treatment!).

There has been an explosion in industry in the last few decades to find drugs and other treatments that can more specifically target, treat, and cure. But it is still considered a high risk field. The number of drugs that were finally approved for treatment represent less than 10% of those initially tested3.

While the complicated combinations of chemotherapy drugs, the precise treatment regiments, and the high doses used have improved the outcome for many, there are still many cancers that are incurable. And even for the very 'curable cancers,' such success doesn't mean much if you are part of the 10%, say, that do not respond well to treatment. Continued work on drug discovery, treatment protocol, and understanding basic biology will help. Still, one looks for that big turn, that big discovery. Who knows what the next discovery will show. Who knows where that will come from. Who knows where that will take us.


1) Morrison, W.B., Cancer Chemotherapy: An Annotated History. J Vet Intern Med. (2010); 24:1249-1262

2) Devita, V.T., Chu, E., A History of Cancer Chemotherapy. Cancer Res (2008); 8:8642-8653

3) Chabner, B.A., Roberts T.G., Chemotherapy and the war on cancer. Nat. Rev. Can. (2005); 5: 65-72

For this post I mainly rehashed the excellent reviews listed above. My sources may be difficult for you to access. The websites below are easy to find and have excellent information and plenty of follow up history. - Evolution of Cancer Treatment - History of Chemotherapy

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