There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality.

Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

I and i

The clinical use of anthracyclines like doxorubicin and daunorubicin can be viewed as a sort of double-edged sword. On the one hand, anthracyclines play an undisputed key role in the treatment of many neoplastic diseases; on the other hand, chronic administration of anthracyclines induces cardiomyopathy and congestive heart failure usually refractory to common medications. Second-generation analogs like epirubicin or idarubicin exhibit improvements in their therapeutic index, but the risk of inducing cardiomyopathy is not abated. It is because of their janus behavior (activity in tumors vis-a-vis toxicity in cardiomyocytes) that anthracyclines continue to attract the interest of preclinical and clinical investigations despite their longer-than-40-year record of longevity. Here we review recent progresses that may serve as a framework for reappraising the activity and toxicity of anthracyclines on basic and clinical pharmacology grounds. We review 1) new aspects of anthracycline-induced DNA damage in cancer cells; 2) the role of iron and free radicals as causative factors of apoptosis or other forms of cardiac damage; 3) molecular mechanisms of cardiotoxic synergism between anthracyclines and other anticancer agents; 4) the pharmacologic rationale and clinical recommendations for using cardioprotectants while not interfering with tumor response; 5) the development of tumor-targeted anthracycline formulations; and 6) the designing of third-generation analogs and their assessment in preclinical or clinical settings. An overview of these issues confirms that anthracyclines remain "evergreen" drugs with broad clinical indications but have still an improvable therapeutic index.

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Anthracyclines: Molecular Advances and Pharmacologic Developments in Antitumor Activity and Cardiotoxicity

The terms 'antioxidant', 'oxidative stress' and 'oxidative damage' are widely used but rarely defined. This brief review attempts to define them and to examine the ways in which oxidative stress and oxidative damage can affect cell behaviour both in vivo and in cell culture, using cancer as an example.

Biochemistry of oxidative stress

Oxidative stress occurs when the production of potentially destructive reactive oxygen species (ROS) exceeds the bodies own natural antioxidant defenses, resulting in cellular damage. Oxidative stress is a common pathology seen in approximately half of all infertile men. ROS, defined as including oxygen ions, free radicals and peroxides are generated by sperm and seminal leukocytes within semen and produce infertility by two key mechanisms. First, they damage the sperm membrane, decreasing sperm motility and its ability to fuse with the oocyte. Second, ROS can alter the sperm DNA, resulting in the passage of defective paternal DNA on to the conceptus. This review will provide an overview of oxidative biochemistry related to sperm health and will identify which men are most at risk of oxidative infertility. Finally, the review will outline methods available for diagnosing oxidative stress and the various treatments available.

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Oxidative stress and male infertility—a clinical perspective

The goal of this study is to give a brief background on the literature supporting the PharmGKB pathway about doxorubicin action, and provides a summary of this active area of research. The reader is referred to recent in-depth reviews [1–4] for more detailed discussion of this important and complex pathway. Doxorubicin is an anthracyline drug first extracted from Streptomyces peucetius var. caesius in the 1970’s and routinely used in the treatment of several cancers including breast, lung, gastric, ovarian, thyroid, non-Hodgkin’s and Hodgkin’s lymphoma, multiple myeloma, sarcoma, and pediatric cancers [5–7]. A major limitation for the use of doxorubicin is cardiotoxicity, with the total cumulative dose being the only criteria currently used to predict the toxicity [4,8]. As there is evidence that the mechanisms of anticancer action and of cardiotoxicity occur through different pathways there is hope for the development of anthracycline drugs with equal efficacy but reduced toxicity [4]. Knowledge of the pharmacogenomics of these pathways may eventually allow for future selection of patients more likely to achieve efficacy at lower doses or able to withstand higher doses with lesser toxicity. We present here graphical representations of the candidate genes for the pharmacogenomics of doxorubicin action in a stylized cancer cell (Fig. 1) and toxicity in cardiomyocytes (Fig. 2), and a table describing the key variants examined so far.






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Fig. 1


Graphical representation of the candidate genes involved in the pharmacodynamics of doxorubicin in a stylized cancer cell. A fully interactive version of this pathway is available online at PharmGKB at http://www.pharmgkb.org/do/serve?objId=PA165292163o ROS, reactive oxygen species.

Doxorubicin pathways: pharmacodynamics and adverse effects

Adult growth hormone deficiency (GHD), a condition characterized by increased oxidative stress, is related to augmented cardiovascular, metabolic and oncological risk. A case-control observational study has been performed to evaluate DNA oxidative damage analysing the production of thymidine-glycol in lymphocytes and its correlation with plasma antioxidant levels, evaluated as Total Antioxidant Capacity (TAC). GHD was diagnosed using GHRH 50μg iv+arginine 0,5 g/Kg test, with peak GH response 30 kg/m2. Three groups were identified: total GHD (n = 16), partial GHD (n = 11), and controls (n = 12). Thymidine-glycol, TAC and IGF-1 have been determined respectively in lymphocytes, plasma and serum samples. When considering thymidine-glycol, we found a significant difference between total vs partial GHD and controls. Unexpectedly thymidine-glycol was lower in total GHD, also accompanied with a significant increase in plasmatic TAC. Our results showed that in adult GHD condition, the production of antioxidant species, in response to increased oxidative stress, could exert a protective effect on thymidine-glycol formation, and consequently on DNA intracellular damages. This pilot study could be inserted in the complex scenario of oxidative damage of GHD, a subtle, yet poorly defined condition, worthy of further insights.

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Can plasma antioxidants prevent DNA damage in oxidative stress condition induced by growth hormone deficiency? A pilot study.

Ascorbic acid, isoascorbic acid and dehydroascorbic acid quench the tryptophyl fluorescence of alkaline phosphatase. The quenching is protein aspecific, although its extent reflects the different inhibitory efficiency of the compounds. The kinetic inactivation and emission deactivation of alkaline phosphatase isoenzymes present also striking similarities. The fluorescence modifications, moreover, show a particular pattern, indicative of a transition phenomenon. The quenching effects displayed by the ascorbic system on alkaline phosphatase can then supply an interesting insight into other aspects of the inhibitor-enzyme interaction.

Modifications induced by ascorbic acid on alkaline phosphatase fluorescence.

Back Pain (BP) is a common medical problem; anabolic hormones, through the modulation of oxidative stress (OS), could influence fracture risk. We evaluated the prevalence of anabolic hormonal deficiencies and their relationship with OS in males with BP, associated or not to nontraumatic fractures. 49 males with BP, from 36 to 80 years, were divided in two groups according to radiological evidence of nontraumatic fractures; group A (n=25): non-fractured; group B (n=24): fractured. A different prevalence of hormonal deficits was observed: 24% of hypotestosteronemia in A, 0% in B; 16% of GHD in A, 29% in B; Total Antioxidant Capacity (TAC) showed a trend toward higher levels in B. In A, despite lower TAC, a significant inverse correlation was present between TAC and IGF-1. A greater prevalence of GHD in patients with vertebral fractures was seen and, in a subgroup, OS could mediate the deleterious effects of hyposecretory GH state.

Oxidative stress and anabolic hormones in back pain: Current concept and preliminary analysis in male cohort

Fluorescence studies of ascorbate-melittin interaction

A kinetic approach is described which enables the measurement of the enzyme inactivation rate constant during the reaction course. A mathematical analysis is presented and it is shown that a time-dependent step may be postulated to exist. Reaction kinetics follow an exponential rule with time as the independent variable and enzymatic activity as the dependent variable. A simple procedure of graphical analysis is reported and the influence on the inactivation rate constant of various conditions (temperature and inhibitor concentration) is evaluated. The method is illustrated by an experimental model: the inactivation of bovine kidney alkaline phosphatase by urea.

Elisabetta Meucci

Papers

Can plasma antioxidants prevent DNA damage in oxidative stress condition induced by growth hormone deficiency? A pilot study.

Modifications induced by ascorbic acid on alkaline phosphatase fluorescence.

Oxidative stress and anabolic hormones in back pain: Current concept and preliminary analysis in male cohort

Fluorescence studies of ascorbate-melittin interaction

A kinetic approach to the evaluation of alkaline phosphatase inactivation by urea.