Howard Skipper and the treatment of ALL
One man deserves special mention in this tale of ara C and childhood ALL. His name is Howard Skipper. Skipper ushered drugs from trials in tissue culture to human trials. The book, The Cure of Childhood Leukemia, into the age of miracles [12, online article], devotes an entire chapter to Howard Skipper. He called himself a "mouse doctor" and the book states that his "insights were critical to the remarkably quick development of effective chemotherapy for leukemia in the mid- to late 1960s". Skipper states "we discovered that two drugs, cytosine arabinoside and 6-thioguanine, both antimetabolites, worked well in adults with acute myelogenous leukemia after we first modeled them in animals."
Skipper's research employed the mammalian cancer cell line named L-1210 (The same one used in the first ara C mammalian studies [5]). This cell line can be injected into mice, resulting in the mice developing leukemia. Skipper studied the growth of the leukemia cells in mice and the effect that various combinations of drugs had on the growth of these cells. One of the drugs that he studied was ara C.
Freireich and Skipper are co-authors of one of the "Citation Classics" I discussed in an earlier section (Citation Classics, number 14, 1986). [13] This frequently-cited paper is credited with being the first systematic effort to correlate how much of an anticancer drug animals can tolerate with how much of that same drug humans are likely to tolerate. This made it possible for doctors to begin clinical trials with a pretty good idea of how much of the drug they could give people without killing them. The relationship is not a simple weight or relationship between body size and drug dose, instead, it is a correlation with units of body surface area.
In 1982, Skipper was awarded with the prestigious Charles F. Kettering Prize for "the conceptual and experimental contributions that led to cures of acute leukemia, lymphoma and solid tumor malignancies". Read Skipper's biography on the Alabama Academy of Honor web site.
Summary so far
And there we have it, our tale of from the sea to ara C, a successful chemotherapy agent for killing cancer cells in children with ALL. A young scientist, Bergmann, swimming around in the ocean and collecting sea sponges then plunging them into acetone. His curiousity about the crystals that appeared, his determination to figure out what the crystals were, and finding them to be an unnatural nucleoside that he named spongothymidine. Cohen taking up the task of figuring out the effect a synthetic relative to spongothymidine - ara C - on DNA synthesis. In the 1960s, numerous research groups studying various aspects and effects of ara C in bacterial and mammalian systems. Skipper ushering ara C from the lab bench to treatment for childhood ALL. Today (2005), ara C is still included in the combination of 4-7 chemotherapy drugs employed in all of the current COG protocols for first-remission ALL.
It is a story of how the curiousity of scientists can lead to the saving of lives. Why did they plunge the sponges into boiling acetone in the first place? I don't know, but I'm glad they did.
Two other drugs used in childhood ALL also have roots in natural products. Thes drugs are vincristine and the anthracyclines.
The discovery of the spongonucleosides did not immediately inspire scientists to go to the sea to search for more drugs. However, the last decade or so has seen a resurgence of interest in searching for new drugs from the barely-tapped resources in the sea. [14-20] Many of these contemporary papers credit the sponge nucleosides with inspiring the development of the arabinosyl nucleoside drugs both as anticancer and antiviral agents. Check out the bibliography if you are interested in reading these articles (some of them are online and I have included links when possible).
Quite recently, more analogues of nucleosides have been designed, synthesized, and found to be active against cancer cells in general and childhood ALL cells in particular. These are presented in the final section.