Доксорубицин: применение, побочные эффекты и кардиотоксичность

Chemotherapy medication

Doxorubicin was approved for medical use in the United States in 1974. It is on the World Health Organization's List of Essential Medicines. Doxorubicin was originally made from the bacterium Streptomyces peucetius.

In the EU doxorubicin pegylated liposomal (as Caelyx) is indicated to treat breast cancer, ovarian cancer, and AIDS related Kaposi's sarcoma. It is indicated to treat multiple myeloma in combination with bortezomib. Doxil (see below) is used primarily for the treatment of ovarian cancer where the disease has progressed or recurred after platinum based chemotherapy, or for the treatment of AIDS related Kaposi's sarcoma.

The most dangerous side effect of doxorubicin is dilated cardiomyopathy, leading to congestive heart failure. The rate of cardiomyopathy is dependent on its cumulative dose, with an incidence about 4% when the dose of doxorubicin is 500–550 mg/m2, 18% when the dose is 551–600 mg/m2 and 36% when the dose exceeds 600 mg/m2. There are several ways in which doxorubicin is believed to cause cardiomyopathy, including oxidative stress, downregulation of genes for contractile proteins, and p53 mediated apoptosis. There is no effective treatment against established cardiomyopathy caused by the drug as of 2010.

Another common and potentially fatal complication of doxorubicin is typhlitis, an acute life threatening inflammation of the bowel. Additionally, some people may develop PPE, characterized by skin eruptions on the palms of the hand or soles of the feet, swelling, pain, and erythema. 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.

There is a pegylated (polyethylene glycol coated) liposome encapsulated form of doxorubicin, developed to treat Kaposi's 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. This liposome encapsulated form is also approved by the FDA for treatment of ovarian cancer and multiple myeloma. A non pegylated liposomal doxorubicin, called Myocet, is approved in the European Union and in Canada for the treatment of metastatic breast cancer in combination with cyclophosphamide, but it has not been approved by the FDA for use in the United States. Unlike Doxil, the Myocet liposome does not have a polyethylene glycol coating, and therefore does not result in the same rate of PPE. The minimization of this side effect may allow for one for one (1:1) substitution with doxorubicin in the same treatment regimen, thereby improving safety with no loss of efficacy. Like Doxil, the liposomal encapsulation of the doxorubicin limits the cardiotoxicity. In theory, by limiting the cardiotoxicity of doxorubicin through liposomal encapsulation, it can be used safely in concurrent combination with other cardiotoxic chemotherapy drugs, such as trastuzumab. There is an FDA black box warning that trastuzumab cannot be used in concurrent combination with doxorubicin, only in sequential combination. Though concurrent combination of trastuzumab and doxorubicin in clinical studies found superior tumor response, the combination resulted in unacceptable cardiotoxicity, including risk of cardiac failure manifesting as congestive heart failure (CHF). Published phase II study results have shown that Myocet, trastuzumab, and paclitaxel can safely be used concurrently without the cardiac risk, as measured by reduction in LVEF function, while still achieving superior tumor response. This finding is the basis for the ongoing phase III trial for FDA approval. This strain was created by Arcamone et al. in 1969 by mutating a strain producing daunorubicin, but not DXR, at least in detectable quantities. Subsequently, Hutchinson's group showed that under special environmental conditions, or by the introduction of genetic modifications, other strains of Streptomyces can produce doxorubicin. His group also cloned many of the genes required for DXR production, although not all of them have been fully characterized. In 1996, Strohl's group discovered, isolated and characterized dox A, the gene encoding the enzyme that converts daunorubicin into DXR. By 1999, they produced recombinant dox A, a cytochrome P450 oxidase, and found that it catalyzes multiple steps in DXR biosynthesis, including steps leading to daunorubicin. This was significant because it became clear that all daunorubicin producing strains have the necessary genes to produce DXR, the much more therapeutically important of the two. Hutchinson's group went on to develop methods to improve the yield of DXR, from the fermentation process used in its commercial production, not only by introducing dox A encoding plasmids, but also by introducing mutations to deactivate enzymes that shunt DXR precursors to less useful products, for example baumycin like glycosides. 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.

[[Image:Doxorubicin–DNA complex 1D12. png|thumb|Diagram of two doxorubicin molecules intercalating DNA, from 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. 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, the DNA damage response, epigenome and transcriptome are deregulated in doxorubicin exposed cells. Clinical trials began in the 1960s, and the drug was successful in treating acute leukemia and lymphoma. However, by 1967, it was recognized that daunorubicin could lead to fatal cardiac toxicity. Researchers at Farmitalia soon discovered that changes in biological activity could be made by minor changes in the structure of the compound. A strain of Streptomyces was mutated using N nitroso N methyl urethane, and this new strain produced a different, red colored antibiotic. They named this new compound Adriamycin, after the Adriatic Sea, and the name was later changed to doxorubicin to conform to the established naming convention. Doxorubicin and daunorubicin together can be thought of as prototype compounds for the anthracyclines. Subsequent research has led to many other anthracycline antibiotics, or analogs, and there are now over 2,000 known analogs of doxorubicin. By 1991, 553 of them had been evaluated in the screening program at the National Cancer Institute (NCI).

On 24 March 2022, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Zolsketil pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS related Kaposi's sarcoma. Zolsketil pegylated liposomal was approved for medical use in the European Union in May 2022. On 21 July 2022, the CHMP adopted a positive opinion, recommending the granting of a marketing authorization for the medicinal product Celdoxome pegylated liposomal, intended for the treatment of metastatic breast cancer, advanced ovarian cancer, progressive multiple myeloma and AIDS related Kaposi's sarcoma. Celdoxome pegylated liposomal is a hybrid medicine of Adriamycin which has been authorized in the EU since 24 October 1979. It is sold under a number of different brand names, including Adriamycin PFS, Adriamycin RDF, or Rubex.

Combination therapy experiments with sirolimus (rapamycin) and doxorubicin have shown promise in treating Akt positive lymphomas in mice. Further, the release of photo activated adriamycin with the aid of nanoporous optical antenna resulted in significant anti cancer effect in MCF 7 breast cancer cells. In 2006, animal research coupling a murine monoclonal antibody with doxorubicin created an immunoconjugate that was able to eliminate HIV 1 infection in mice.

There is some evidence for antimalarial activity for doxorubicin and similar compounds. In 2009, a compound similar in structure to doxorubicin was found to inhibit plasmepsin II, an enzyme unique to the malarial parasite Plasmodium falciparum. The pharmaceutical company GlaxoSmithKline (GSK) later identified doxorubicin in a set of compounds that inhibit parasite growth.

Doxorubicin is also known to be fluorescent. This has often been used to characterize doxorubicin concentrations, and has opened the possibility of using the molecule as a theranostic agent. However, there are significant limitations, as doxorubicin's fluorescence spectrum is known to depend on a variety of factors, including the pH of the environment, solvent dielectric constant and others. Doxorubicin fluorescence is quenched by binding to DNA, and shielded by micelle encapsulation. It is also known to self quench at high concentrations. In contrast, histone binding amplifies fluorescence.