Doxorubicin
History and Discovery
Obligatory—This is not medical advice
It’s rare that the true story behind a treatment is heard. I find that odd, as the tales are often amazing and very human—with drama as well as unique insights. Books like ‘Cancer: The Emperor of All Maladies’ have shown that there is broad appeal to shining a light on the early days of therapy for cancer. People like to know where their food, technologies, and treatments come from. I think that we owe it to our patients to be able to recount the benefits, drawbacks, and history of treatments that we recommend. It’s for that reason that I will begin to describe the early days of doxorubicin here.
Discovery
To comprehend the background of doxorubicin, one must have a context from which to build. The mid-1900s led to myriad developments in medical research. A small portion of them is listed here, including the first FDA approval in cancer. Advancements at that time were incremental with decades between discovery of new, generally cytotoxic, therapies. Many of those medications were products of bacteria or plant life. Streptomyces was notable for having been the genesis of multiple medications: streptomycin, chloramphenicol, etc. Motivated by this, Farmitalia Research Laboratories, headquartered in Milan, Italy, initiated a campaign to isolate substances from micro-organisms, including Streptomyces. Aurelio Di Marco led much of this research. In one particular culture of Streptomyces, a vibrantly red pigment emerged and was found to weakly inhibit the growth of gram positive rods (a large group of bacteria). Remarkably, it demonstrated highly effective anticancer properties in mouse models. This substance would eventually be named daunorubicin or daunomycin.1 A mechanism of action was posited, as daunorubicin readily complexed with DNA in vitro. 2
This medication went on to have a large degree of success as part of treatment for patients with hematologic malignancies, and continues to be given to this day.3
Doxorubicin
Federico Arcamone, aware of the considerable variability in efficacy among previous antibiotics due to minor chemical formula alterations, sought to modify the original strain of Streptomyces, which produced daunorubicin, known as Streptomyces peucetius. To achieve this, he subjected the bacteria to nitrogen mustards, resulting in the development of a new strain called Streptomyces peucetius var. caesius.4
As seen above, a single group on carbon 14 of daunorubicin was changed, from a hydrogen to a hydroxyl group. Surprisingly, this seemingly minor alteration had substantial effects on animal models and the control of solid tumors. In contrast to daunorubicin, doxorubicin was discovered to elicit responses in various malignancies, spanning from soft tissue sarcoma to lymphoma. I believe the history of the clinical development of doxorubicin warrants a separate post and I will defer further discussion until then.
Closing Thoughts
Doxorubicin is an anti-tumor antibiotic which is derived from Streptomyces peucetius var caesius. Despite its chemical similarity to daunorubicin, it exhibits a distinct clinical spectrum of activity. Its origins trace back to the 1960s when it was first produced. Despite its age, doxorubicin continues to be one of the more broadly administered chemotherapies to this day. In the future, we will explore the initial clinical trials conducted with this medication and how these paved the way for FDA approval in 1974.
https://www.nature.com/articles/201706a0
https://pubmed.ncbi.nlm.nih.gov/4290058/
https://www.nccn.org/