Therapy Analysis - Anticancer drugs
Previous & Present Attempts at tackling Cancer
Previous attempts to overcome these issues included altering amino acid sequences to reduce antigenic sideeffects and enzyme degradation, as well as coupling the therapeutic proteins to immunoglobulins or albumin, or packaging them in liposomes. These methods were not sufficient to overcome all the problems encountered, however. In the late 1970s, Frank Davis, Abraham Abuchowski and colleagues pioneered the development of the now well-established process of conjugating polyethylene glycol to proteins, in a process known as pegylation. This increases solubility, stability and circulating life, protects against degradation and reduces the required dosing frequency without affecting efficacy. Other advantages to pegylation are intact elimination from the body via the kidneys or faeces, a lack of immunogenicity, and the fact that PEG chains have little to no toxicity associated with their use.
At present there are 3 pegylated anticancers on the market. These include pegaspargase (Oncaspar), a pegylated L-aspirginase developed by Enzon for acute lymphoblastic leukaemia, amongst other haematological cancers. It has reduced toxicity, especially in regards to allergic reactions, compared to the native protein. There is also pegfilgrastim (Neulasta), a long acting version of filgrastim, developed for improved treatment of neutropenia, a side effect of chemotherapy. Finally there is Doxil, a pegylated liposomal formulation of doxorubicin developed by Alza (Johnson & Johnson) for use in a variety of cancers, including Kaposi's sarcoma. Doxorubicin is an anthracyline antibiotic first developed in the 1950s.
Early in the 20th century, Paul Ehrlich proposed the concept of the "magic bullet": a concept suggesting the introduction of a therapeutic compound in a perfected drug carrier into a patient, which transports itself precisely to the disease target and delivers the exact required dose of a drug to treat the condition. The development of anticancers is a perfect example of the pursuit of this goal over the past 60 years, beginning with the discovery of drugs that kill cancer cells, to the progression to chemically altering drugs to improve their performance, and of course including the contribution of biologically-based therapeutics both for their reduced toxicity, and increased tumour-targeting specificity. With the advent of the human genome project arose the possibility to finally comprehend all the elements underlying why a cell becomes the 'enemy within'. The next years of oncological research can now build on this body of knowledge, which may lead to a fulfilment of so many people's desire, including Nixon's, to finally defeat 'The Big C'.
Alix Biancardi
Image courtesy of the National Museum of Health and Medicine,
Armed Forces Institute of Pathology, Washington, D.C.
