Some triple mutants, that also over-expressed dox A, were able to double the yield of DXR. This is of more than academic interest, because at that time DXR cost about $1.37 million per kg and current production in 1999 was 225 kg per annum.More efficient production techniques have brought the price down to $1.1 million per kg for the nonliposomal formulation. Although DXR can be produced semi-synthetically from daunorubicin, the process involves electrophilic bromination and multiple steps, and the yield is poor. Since daunorubicin is produced by fermentation, it would be ideal if the bacteria could complete DXR synthesis more effectively. Mechanism of action
Doxorubicin interacts with DNA by intercalation and inhibition of macromolecular biosynthesis. This inhibits the progression of topoisomerase II, an enzyme which relaxes supercoils in DNA for transcription. Doxorubicin stabilizes the topoisomerase II complex after it has broken the DNA chain for replication, preventing the DNA double helix from being released and thereby stopping the process of replication. It may also increase quinone type free radical production, hence contributing to its cytotoxicity.The planar aromatic chromophore portion of the molecule intercalates between two base pairs of the DNA, while the six-membered daunosamine sugar sits in the minor groove and interacts with flanking base pairs immediately adjacent to the intercalation site, as evidenced by several crystal structures.By intercalation, doxorubicin can also induce histone eviction from transcriptionally active chromatin. As a result, DNA damage response, epigenome and transcriptome are deregulated in doxorubicin-exposed cells.
Due to these side effects and its red color, doxorubicin has earned the nickname "red devil" or "red death. "Chemotherapy can cause reactivation of hepatitis B, and doxorubicin-containing regimens are no exception.Doxorubicin and several chemotherapeutic drugs (including cyclophosphamide) can cause a loss of skin pigmentation. Liposomal formulations
There is a pegylated (polyethylene glycol coated) liposome-encapsulated form of doxorubicin, developed to treat Kaposis sarcoma The polyethylene glycol coating results in preferential concentration of doxorubicin in the skin. However, this also results in a side effect called palmar plantar erythrodysesthesia (PPE), more commonly known as hand-foot syndrome. Following administration of this form of doxorubicin, small amounts of the drug can leak from capillaries in the palms of the hands and soles of the feet. The result of this leakage is redness, tenderness, and peeling of the skin that can be uncomfortable and even painful. In clinical testing at 50 mg/m2 dosing every 4 weeks, half of people developed hand-foot syndrome. The rate of this side effect limits the dose of this formulation that can be given as compared with plain doxorubicin in the same treatment regimen, thereby limiting potential substitution. Substitution would be desirable because liposome-encapsulated doxorubicin is less cardiotoxic than unencapsulated doxorubicin.