Adriamycin

Adriamycin, a trade name of Doxorubicin, is an anti-cancer chemotherapy drug.¹ It is used to treat cancer, leukemia and lymphoma. Doxorubicin can damage DNA, may slow or stop cancer cells by harms cancer cells causing their death.² Doxorubicin is an antibiotic belong to a class of medication called anthracycline antibiotics. The source of Doxorubicin is natural product produced by soil fungus Streptomyces. ²

Adriamycin, it is red in color and is administered via an intravenous (IV) injection. There is no pill form of Doxorubicin. Adriamycin for injection is supplied as a sterile red-orange lyophilized powder in single dose flip-top vials. In the developing world, the wholesale cost is about 3.88 to 32.79 USD per 50mg vial.¹¹ In the United Kingdom this amount cost about £100.12.¹²

It is important to understand the mechanism of action. The research done at the University of Texas Medical Center, shown that doxorubicin can combat tumours via a mechanism called regulated intramembrane proteolysis.⁶ Membrane-bound protein is cleaved in this process and will release soluble messaging molecules. The study found that a membrane protein, CREB3L1 with a carboxyl and amino terminal undergoes proteolytic cleavage during viral infection and release amino-terminal domain. Then it will translocate to nucleus, intercalates between base pairs in the DNA helix, and change the transcription, preventing DNA replication, and ultimately inhibit cellular proliferation.⁶

The history of the antitumor anthracyclines begins in late 1950s when a pigmented compound. In May 1960, a pioneering and fruitful agreement has been signed for the discovery and development up to clinical trials of new natural antitumor agents.³ The first anthracyclines β-rhodomycin II, originated from a strain of Streptomyces.⁹ Although β-rhodomycin II displayed potent anti-bacterial activity in culture, the high toxicity in mice led to some early studies to identify the structure feather and different substitution.⁴ In 1960s, Doxorubicin was isolated and the structure was elucidated. Adriamycin, one of the best drug was discovered and developed in Milan.

The first vials of Adriamycin sent to be tested for clinical trial in July 1969.³ and was approved by FDA on 1993 (Company Adria Laboratories), was licensed by Pfizer. And now, Adriamycin is still amongst the most widely prescribed and effective anticancer agents.⁴

In 2015 the global market size for doxorubicin was valued at USD 809.6 million. The annual compound growth rate is predicted to be 6.4% over the forecast period. Doxorubicin used to treat breast cancer held the majority of the market, share over 21%.¹³ The cancer incidence would further increased by 50% by 2020, according to the World Health Organization (WHO). And WHO estimates there were 8.2 million deaths to cancer. The growing prevalence of the disease and other factors is going to boost the market for doxorubicin in the forecast period.¹³

In 1998, Early Breast Cancer Trialists Collaborative Group (EBCTCG) have established the clinical studies of the effectiveness of doxorubicin-containing regimens in early stage breast cancer. In six random trials, 3510 women in total with early stage breast cancer were evaluated, as the results, 1745 first recurrence and 1348 deaths had occurred.¹⁴

However, this drug can cause short and long term cardiotoxicity even under a lower dose. Children and adolescents appears to be particularly cardiotoxic sensitive of doxorubicin.⁵ Therefore, the clinical use of Adriamycin has been limited. The cumulative dosage can cause the life-threatening side effects.⁶ Also the formation of oxygen free radicals also contributes to the toxicity.⁷ Some other adverse effects reported, including acute nausea and vomiting, fever, chills urticarial, neurotoxicity, etc.¹⁴ Doxorubicin has earned a nick name “red devil” due to these side effects and its red color.¹⁵

Doxorubicin only be administered under the supervision of qualified physicians experienced in the use of cytotoxic therapy. Before start the treatment with doxorubicin, patients should recover from the prior cytotoxic treatment. Also, a careful baseline assessment of blood counts is also important before initial the treatment with doxorubicin. Patients should be carefully monitored during the treatment.¹⁶ Doxorubicin alone has been assigned a Pregnancy Category D by the FDA. Doxorubicin can cause fetal harm when administered to a pregnant woman. Dose for pregnant woman is about 1/13 the recommended human dose. The best way is to talk to your doctor to prevent pregnancy while receiving Doxorubicin.¹⁶

Due to the side effect, previous clinical studies have focused on lower toxicity and better tolerability. Liposomal formulations of doxorubicin was discovered.⁸ The first liposomal encapsulate anticancer drug received clinical approval was Doxorubicin hydrochloride liposomal injection. Doxorubicin liposomal have equal efficacy with less side effect.⁸ However, are more expensive.¹²

In a conclusion, Adriamycin, a cancer medication, can interfere the growth and spread of cancer, which is produced by genetic modification of Streptomyces. Now, Adriamycin is still amongst the most widely prescribed and effective anticancer agents. Adriamycin hold a large market size and predict will have an increased furfure market.  However, this drug has recognized to produce cardiac toxicity and other adverse effects. In order to reduce the toxicity, Doxorubicin liposomal was discovered.

References and bibliography

1.     "Doxorubicin Hydrochloride". The American Society of Health-System Pharmacists. Archived from the original on 11 October 2016. Retrieved 12 January 2017.

2.     Doxorubicin (Adriamycin®, Rubex®): Cancer Drug Information | CTCA. (0001, January 01). Retrieved from https://www.cancercenter.com/cancer-drugs/doxorubicin/

3.     Cassinelli, G. (2016). The Roots of Modern Oncology: From Discovery of New Antitumor Anthracyclines to their Clinical Use. Tumori Journal, 102(3), 226-235. doi:10.5301/tj.5000507

4.     Lown, J. W. (1993). Discovery and development of anthracycline antitumour antibiotics. Chemical Society Reviews, 22(3), 165. doi:10.1039/cs9932200165

5.     Chorghade, E. S. (2006). Drug Discovery and Development, Volume 1, Drug Discovery. John Wiley & Sons.

6.     Patel, A. G., & Kaufmann, S. H. (2012). How does doxorubicin work? ELife, 1. doi:10.7554/elife.00387

7.     NCI Drug Dictionary. (n.d.). Retrieved from https://www.cancer.gov/publications/dictionaries/cancer-drug/def/doxorubicin-hydrochloride-liposome

8.     Rivankar, S. (2014). An overview of doxorubicin formulations in cancer therapy. Journal of Cancer Research and Therapeutics, 10(4), 853. doi:10.4103/0973-1482.139267

9.     Discovery and Development of Doxorubicin. (1981). Medicinal Chemistry Doxorubicin - Anticancer Antibiotics, 1-47. doi:10.1016/b978-0-12-059280-7.50007-9

10.  Heger, Z., Cernei, N., Kudr, J., Gumulec, J., Blazkova, I., Zitka, O., . . . Kizek, R. (2013). A Novel Insight into the Cardiotoxicity of Antineoplastic Drug Doxorubicin. International Journal of Molecular Sciences, 14(11), 21629-21646. doi:10.3390/ijms141121629

11.  "Doxorubicin HCL". International Drug Price Indicator Guide. Retrieved 8 December 2016.

12.  British national formulary : BNF 69 (69 ed.). British Medical Association. 2015. p. 583. ISBN 9780857111562.

13.  Doxorubicin Market Size - Segmented by Drug Formulation (Lyophilized Powder and Doxorubicin Injection), Application, Distribution Channel, and Geography - Growth, Trends, and Forecast (2018 - 2023). (n.d.). Retrieved from https://www.mordorintelligence.com/industry-reports/doxorubicin-market

14.  Comparisons between different polychemotherapy regimens for early breast cancer: Meta-analyses of long-term outcome among 100 000 women in 123 randomised trials. (2012). The Lancet, 379(9814), 432-444. doi:10.1016/s0140-6736(11)61625-5

15.  Bloch, Richard; Bloch, Annette. "25 Most Asked Questions". Fighting Cancer. R. A. Bloch Cancer Foundation. Archived from the original on June 26, 2007. Retrieved 2007-06-28.

16.  Doxorubicin Hydrochloride Injection USP. (n.d.). Retrieved from https://dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=e0349f98-42fa-4003-b6d8-a1db1401b0ef&type=display