Actinomycin D was the first antitumor antibiotic isolated from Streptomyces parvallus cultures by the lab of 1952 Nobel laureate, Dr Selman Waksman, at Rutgers University. However, it took a young Chinese physician and the confidence in her by a future US Surgeon General for this natural product drug to positively impact the lives of children with cancer.
An unusually engaging Boston Globe obituary by Gloria Negri caught my attention this week that announced the death of pediatric oncology pioneer, Charlotte Tan (Hsu), MD, of pneumonia on 1 April in Brookline, MA. Dr Tan's 1959 paper in Pediatrics yielded our first insights on the potential benefit of actinomycin D in Wilms' tumor and childhood leukemias and lymphomas (The structure below is taken from that paper).
Known often as dactinomycin, the drug also went on to be used in rhabdomyosarcoma. However, most researchers today probably only know the drug as a laboratory tool to inhibit RNA polymerase activity or in the form of its fluorescent DNA-intercalating analog, 7-amino-actinomycin D (7-AAD), used to stain DNA in microscopy and cellular flow cytometry-based apoptosis methods.
Regular readers may know how deeply I revere pioneers in basic and clinical and cancer research; many of these researchers just happen to be women, including my idol, 1988 Nobel laureate Gertrude (Trudy) Elion for her work on antimetabolite chemotherapy. I'm just thinking out loud here but I wonder if the pioneering work of women in the cancer field had something to do with that group of diseases attracting professionals possessing a greater depth of compassion than your average Y-chromosome bearer.
Be that as it may, Dr Tan's story is fascinating:
Charlotte Tan Hsu was born in Kiang-Si, China. She earned her medical degree at Xiangya Medical College in 1947 and interned at Nanjing's Central Hospital. When the Communists took over China, Dr. Tan left on a freighter for New York and first worked at St. Barnabas Hospital in Newark.
Word of her work in childhood cancer in China had traveled to this country, and Charles Everett Koop, a pediatric surgeon at Children's Hospital in Philadelphia who went on to become US surgeon general, brought Dr. Tan there. In 1952, she joined the staff of Sloan-Kettering. . .
. . .Colleagues said Dr. Tan was one of the country's leading pediatric oncologists during her more than four decades at the Memorial Sloan-Kettering Cancer Center in New York City, where she was vice chairman for developmental therapeutics from 1974 to 1996, when she retired.
In particular, she was the first to explore the use of several cancer drugs in the treatment of childhood malignancies, said Dr. Richard O'Reilly, chairman of the department of pediatrics at Sloan-Kettering. O'Reilly said Dr. Tan's studies of such drugs as dactinomycin led to their introduction into multidrug regimens to treat children with leukemia and cancers of developing bone, muscle, and nerve cell.
While actinomycin D is viewed today as having broad toxicity and has been replaced in many pediatric oncology settings, we often fail to appreciate the faith and fortitude of physicians like Dr Tan and her patients and their families in participating in clinical trials. While we still have far to go in treating childhood cancers, imagine being the parent of a child with cancer when Dr Tan began practicing - when there were little or no other choices for treatment:
She worked tirelessly, he [Dr O'Reilly] said, "to ensure that the most promising new drugs would be available to children with cancer early in their development and successfully treated hundreds of young patients who are now cured, healthy adults leading productive lives throughout the world."
Many of those success stories gather annually at Sloan-Kettering to pay tribute to the doctors, like Dr. Tan, who saved their lives. In 1990, an article in Good Housekeeping described the reunions, which attracted a large group of adult survivors of childhood cancer, and pointed out that "20-odd years ago, a photograph such as this could not have been taken - there would have been too many empty spaces."
Despite her tremendous dedication to pediatric oncology, Dr Tan led a vibrant, enriching, and fulfilling life outside of the clinic and lab, according to her daughter, Alicia Hsu:
[W]hile she and her mother were in New York her father lived overseas in Hong Kong during the years she was growing up. Hsu recalled that their home "was always filled with exchange students from China, church friends, and family. Mother loved to cook elaborate Chinese meals of colorful and fragrant dishes."
She spoke of her mother's embrace of Christianity. "I grew up knowing that my mother was on a mission from God to ease the suffering of children and their families who faced childhood cancer," she said.
"Mother was an inspiration for hundreds of people: hospital colleagues, medical students, church leaders, theological students, nieces, nephews, friends, and neighbors," Hsu said.
It's been 25 years since my first pharmacology class and, sadly, I had never heard of Dr Tan before this week.
I wished we learned more about these pioneers while they were still alive. We all have them at our respective institutions but they may be hidden away, relegated to some office down the hall by administration to make room for the next generation of big grant players and clinical "thought leaders."
So seek out your local legends while they are still with us, even the ones who appear cranky on the surface. Buy them lunch, a coffee, a beer and just listen. The stories they can tell will surprise you and their examples of inspiration and perseverance will stay with you.
Addendum (6 April 2008): The NYT's Jeremy Pearce has an even more deeply researched obituary for Dr Tan, noting her 1953 Blood paper on the use of 6-mercaptopurine and later work with daunomycin (daunorubicin) and L-asparaginase. To bring this story back full circle, 6-mercaptopurine was among Trudy Elion's antimetabolite compounds (while working with co-laureate, George Hitchings) - from a woman chemist to a woman physician - what a great story.
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Thanks for bringing this up! It's an inspiring story.
I am inspired! I've had occasion lately to come into peripheral contact with some of the heroes in my field - I will make a point of thanking them for their contributions, and if I'm lucky maybe they'll share some observations with me.
For a broad view of the history of cancer chemotherapy you might want to check out http://dtp.nci.nih.gov/timeline/noflash/index.htm
It was put together as part of the 50th anniversary of the NCI compound testing program. There's a lot of 2 minute interview clips with some interesting bits of history. Unfortunately nothing about Dr. Tan. The seminar is listed at
https://secure.palladianpartners.com/dtp_symposium/agenda.htm and it includes a link for streaming video. The video is almost 5 hours long, but there is a lot of fascinating history. I'd especially recommend the talk by Vince DeVita. Not many people realize that there was a time when a significant part of the scientific community thought it was a waste of time to work on cancer chemotherapy. He also gives some interesting insights into the people and politics that led to the National Cancer Act of 1971.
DrZZ, indeed, we here at the Terra Sig world headquarters hold NCI's Developmental Therapeutics Program in very high regard. DeVita's keynote address is quite excellent - I also recommend it to readers.
I'm also fond of a 2005 Nature Reviews Cancer historical review by Bruce Chabner and Tom Roberts on the early days of chemo drug development with a few old B&W photos as well.
One interesting note as several of us have been discussing the conundrum of today's physician-scientist - many of the key players in chemotherapy drug development were physicians who also had very active lab programs (not just clinical trials projects). With today's disincentives for physician-scientists in academic medical centers (i.e., get lab training but see more patients because it is a more steady and predictable revenue stream), we are missing out on a key component that defined our history in cancer chemotherapy research.
Thanks for this post. My local NPR station has programs about women in science- I will forward this for consideration.
I am not in medicine and did not learn about Dr. Tan until reading her obituary in the New York Times shortly after she passed. With nearly 80 percent of children and teenagers with cancer now living at least five years or many even cured, she (and the others like her) should be revered as national heroes.
thank you very much
Thank you very much for this story. I was a patient of Dr. Tan's and she was the most amazing person I have ever come across in my entire life. She is not only a hero to me but an inspiration to all. I spoke to her several years before she passed away and she was still the most upbeat and happy person. She is truly missed and I still keep all her letters that we wrote to each other after she retired. She was a true definition of a HERO.
I was probably in one of her earliest actonmycin-D trial groups for Wilms tumor in 1957. Now at age 55, 52 years later, still going strong!