Anthracyclines (or anthracycline antibiotics) are a class of drugs used in cancer chemotherapy derived from Streptomyces bacteria (more specifically, Streptomyces peucetius var. caesius).
These compounds are used to treat a wide range of cancers, including leukemias, lymphomas, and breast, uterine, ovarian, and lung cancers.
Anthracyclines are polyciclic planar molecules containing an aminosugar. They are very liposoluble.
They are part of topoisomerase II-inhibitors, like epipodofillotoxins.
- Daunorubicin and idarubicin are used in ALL, AML.
- Doxorubicin is used in solid tumors like breast carcinome, SCLC, ovary, cervix, bladder, prostate, head and neck tumors; in HL, NHL high grade, MM, sarcomas.
- Anthracyclines are poorly absorbed by os (apart from idarubicin). By ev somministration we have to pay attention not to have extravasation because they are very lesive for tissues.
- Large volume of distribution.
- They don't pass hemato-encefalic-barrier.
- Renal excretion.
- Active and inactive metabolites, toxic ones (cardiotoxicity).
Anthracycline has three mechanisms of action:
- Inhibits DNA and RNA synthesis by intercalating between base pairs of the DNA/RNA strand, thus preventing the replication of rapidly-growing cancer cells.
2.Inhibits topoiosomerase II enzyme, preventing the relaxing of supercoiled DNA and thus blocking DNA transcription and replication.
3.Creates iron-mediated free oxygen radicals that damage the DNA and cell membranes.
- Midollar toxicity (dose-dependent) with loss of neutrophils.
- Gastrointestinal toxicity: diarrhea, nausea, vomiting.
- Cardiotoxicity (for further information, http://www.ncbi.nlm.nih.gov/pubmed/15023436 and http://www.cancernetwork.com/display/article/10165/1389095?verify=0).
MECHANISM OF CARDIAC DAMAGE
Patients treated with doxorubicin have been described in acute and chronic cardiovascular effects. The first, which can develop within a few minutes after administration and include hypotension and rhythm disturbances are usually reversible and easily treatable.
However, doxorubicin is also able to induce chronic myocardial damage, depending on the cumulative dose of drug administered and clinically characterized by hypotension, tachycardia, ventricular dilation and congestive heart failure.It has been calculated that, from 27 to 60% of patients who undergo this event by doxorubicin die because of it.
PATHOGENESIS OF THE CARDIAC DAMAGE
On the pathological, the clinical picture is due to cardiomyopathy with typical histological changes, whose pathogenesis is still under study. The results of the numerous works conducted so far favor the hypothesis that an essential role in anthracycline cardiotoxicity is played by oxygen free radical production as a consequence of reduced enzymatic activity of the complex formation with iron of doxorubicin or, particularly its metabolite alcohol doxorubicinol, which is 20-40 times more active in inhibiting myocardial contractility. The selectivity of the damage on the heart is explained by the fact that in the presence of infarction is poor antioxidant defenses, there is an accumulation of doxorubicin and its metabolites preferential doxorubicinol. A partial proof of this theory is based on the observation that iron chelators substances, such as dexrazoxane, have been able to reduce the myocardial damage from anthracyclines. Dexrazoxane is now used in the clinic for this purpose. Overall, other antioxidant compounds have proved ineffective. They also suggested other possible pathogenic factors of myocardial damage from anthracyclines, including accumulation of intracellular calcium, mitochondrial alterations, production of prostaglandins and histamine, direct damage of myofibrils actomiosiniche.
On a practical level, an important point for the doctor and work towards the prevention of cardiotoxicity by doxorubicin, or at least for its early identification in order to prevent irreversible deterioration of organ function. The approach to be followed is now fairly well encoded. And 'know that the cardiotoxic effects are related to dose and peak concentrations of the drug, which can be largely avoided by administering the drug by continuous infusion, in combination with dexrazoxane cardioprotectors as excluding patients at risk in terms of cardiovascular and still maintaining the cumulative dose below the threshold level of 550 mg/m2. Under these conditions, in fact, was reported at a frequency of cardiotoxicity less than 7%, although more recent statistics suggest higher values. More controversial is the issue instead of more effective methods for monitoring cardiac function, in order to highlight the damage so early.
For further information, see http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2784784/.
MONITORING THE CARDIAC FUNCTION
Is known that the myocardial biopsy is the most sensitive and specific for this purpose, but it is almost unthinkable because of its invasiveness. Your doctor may rely on the electrocardiogram, which may show a reduction of voltage of QRS complex, but especially to measurement by echocardiography or MUGA scan, the parameters of systolic function, such as left ventricular ejection fraction. Reductions of this below the 50% or more of 10% compared to baseline were a clear sign of cardiotoxicity and an indication to the discontinuation of treatment. However, these techniques can give both false positives and false negatives. On the other hand, new monitoring methods such as scintigraphy antimiosina or use of biochemical parameters (serum levels of natriuretic peptide or troponin I) have not yet found a definitive validation.
Recently, the issue of cardiotoxicity is back in the limelight due to the introduction in therapy of new anticancer drugs with original mechanisms of action. There was the unexpected highlight of many cases of cardiotoxicity and, in fact, was once again reiterated that unexpected toxicity may occur when multiple molecules are administered in combination, because of pharmacokinetic or pharmacodynamic interactions of order.
Resistances can develop because of:
- mutation of p53
- overexpression of transporters that extrude the drug from the cell (P-glycoprotein, MRP)
- mutations of the target
- overexpression of enzymes that restrict the damage.
The anthracyclines are some of the most effective anticancer treatments ever developed and are effective against more types of cancer than any other class of chemotherapy agents. Their main adverse effects are heart damage (cardiotoxicity), which considerably limits their usefulness, and vomiting.
The first anthracycline discovered was daunorubicin (trade name Daunomycin), which is produced naturally by Streptomyces peucetius, a species of actinobacteria. Doxorubicin (Adriamycin) was developed shortly after, and many other related compounds have followed, although few are in clinical use.
Available agents include:
Valrubicin, used only to treat bladder cancer
Since they are antibiotics, anthracyclines can kill or inhibit the growth of bacteria, but because they are so toxic to humans, they are never used to treat infections.
This has required a call to greater caution in the use of associations of these new compounds, not only with other anticancer drugs, but also made by other patients. One of the most notable cases was that of enhancement of doxorubicin cardiotoxicity by paclitaxel, the first of the taxanes introduced in therapy. This compound may be associated with hypotension and usually minor disturbances of heart rhythm. An Italian study reported in 1995 a high percentage (around 21%) of major cardiotoxic events in patients with metastatic breast cancer treated with the combination of doxorubicin and paclitaxel. Subsequent clinical studies have confirmed this finding. We have seen that the increased cardiotoxicity is associated with a cumulative dose of doxorubicin greater than 380 mg/m2 and the interval between doses of both drugs was shorter than one hour. The taxane causes a significant reduction in clearance of doxorubicin, an increase of 30% in AUC of the anthracycline and then the total body exposure to the drug. Critical sites of interaction of paclitaxel with doxorubicin or other drugs may be the P-glycoprotein and / or cytochrome P450. Furthermore, paclitaxel appears able to increase the production of cardiotoxic metabolite doxorubicinol.
A similar case occurred more recently with trastuzumab (Herceptin commercially), a humanized monoclonal antibody anti-HER2. HER2 is a receptor type tyrosine kinases belonging to the family of receptors for EGF. It's overexpressed in approximately 20-30% of breast cancer, where it is associated with a worse prognosis and resistance to hormonal treatment. The availability of a monoclonal antibody able to selectively block this receptor, has opened the way for a more biologically targeted therapy for breast cancer. Trastuzumab used alone has shown that it led a number of clinical responses (12-26%) in patients bearers of HER2-positive tumors. Above all, it seems to enhance the effect of chemotherapy leading to an increase of responses and a 25% improvement in overall survival. However, a phase III study reported a high incidence of cardiac dysfunction in patients with advanced breast cancer treated with trastuzumab in combination with doxorubicin (cardiac events in 27% of patients) or paclitaxel (cardiac events in 13 of patients). The data would be confirmed by a study in the adjuvant type, where it was decided to suspend the accrual in a treatment arm in which patients received 4 cycles of AC (doxorubicin + cyclophosphamide) followed immediately by trastuzumab and paclitaxel, for the appearance of an excessive number of events cardiotoxic.
A recent survey of seven major clinical studies on the subject supports the hypothesis that trastuzumab promotes the onset of cardiomyopathy by doxorubicin, but it also seems clear that some cardiac dysfunction may occur even when the drug is used alone, with percentages incidence around 3-7. This would indicate a role for the EGF receptor system in myocardial physiology. Indeed, both receptors HER2 and HER3 or their ligands are expressed in the myocardium, where they would be implicated in the activation of transcription factors such as activator protein 1,
involved in regulating cardiac hypertrophy, and NF-kB, a known promoter of cell survival in response to various types of insults. It was also reported the occurrence of dilated cardiomyopathy in mice in which the HER2 gene had been selectively IgE-deleted ventricular cells. Is therefore conceivable that inactivation of HER2 by trastuzumab can induce cardiotoxicity, particularly by promoting the apoptotic processes induced by doxorubicin or other factors detrimental. It seems clear that the occurrence of cardiotoxicity of trastuzumab is higher if the patient has received prior treatment with anthracyclines. The susceptibility of patients at the onset of this cardiotoxicity may be linked to a specific genetic predisposition. A possible pharmacokinetic interaction between trastuzumab and anthracyclines, however, has yet to be established, although preliminary data have shown only minimal effects on the pharmacokinetics of doxorubicin. On the other hand, there are conflicting results in literature, like those of Ewer et al. That, having examined myocardial biopsies of 6 symptomatic patients without finding any evidence of histologic changes, they conclude that the myocardial damage from trastuzumab is only functional and reversible, allowing in some cases the treatment is resumed.
Results will be clearer by the many ongoing studies that have provided for close monitoring of cardiac function, particularly in order to detect if changes in dose, administration schedule or type of association may influence the occurrence of serious adverse effects and whether it is possible select subgroups of patients in whom there is a safe administration of trastuzumab. Meanwhile, notes the CSM / MCA and drug information bulletin recommended to avoid the simultaneous administration of anthracyclines and trastuzumab, given the long period of trastuzumab in the body, even for a period covering the 22 weeks following its administration. In general, however, still needs to call for caution, remembering that the administration of new combinations of drugs is always inadvisable outside of a controlled clinical trial.
WHAT CAN WE DO?
But what can we do to make the cardiotoxicity by anthracyclines be a very smaller problem?
There are many studies about use of ACE-inhibitors just after the end of chemioterapic treatment. In on of them, it was demonstrated that this use could slow the progression of the left ventricular disfunction in many clinical contests, as in cardiomyopathy anthracyclines-induced.
In an Italian study of year 2007, a group of patients (n= 114) were randomized to the treatment
(n= 56) or not (n= 58) with enalapril. The start of the treatment was predicted one month after the end of chemioterapy and was hold on for 12 months. During this period, several cardiologic controls and repeated misurations of troponin I were made.
It has been considered as primary end point of the study the evidence of cardiotoxicity, defined as a decrease of the LVEF of more than 10 points, associated to a decrease below the normality cut off (50).
As secondary end point, was considered the principal cardiac adverse events such as: 1) sudden death 2) death for cardiac cause 3) pulmonar acute edema 4) cardiac failure 5) arrhytmias that required a farmacological treatment.
Primary end point was reached in 25 patients (43%) of the group control and in none (0%) of the ACE-inhibitor group. The incidence of cardiac events during follow up was significantly more elevated in patients not treated with enalapril.
Furthermore, it was observed a more evident reduction of the LVEF in patients with only transient increase of Tn I.
- Troponina I marker di cardiotossicit da farmaci chemioterapici (rassegna).
Daniela Cardinale1, Maria Teresa Sandri2
1 Unit di Cardiologia
2 Unit di Medicina di Laboratorio, Istituto Europeo di Oncologia, I.R.C.C.S., Milano
- Cardiotossicit dei farmaci antitumorali: cautele nell'utilizzo di nuovi agenti
Maria Meli e Natale D'Alessandro - Dipartimento di Scienze Farmacologiche, di Pal