Multicellular resistance: a paradigm for clinical resistance?

Research on resistance to cancer treatment was mainly focused for 20 years on multidrug resistance (MDR). No useful method of reversing MDR, suitable for clinical use, has yet emerged from this large quantity of work. The reason could be an inadequate evaluation of the target. When grown in spheroids, cancer cells exhibit a phenomenon known as 'multicellular resistance' (MCR). Tumours in patients seem to present the same characteristics. The mechanisms underlying MCR can be classified into two forms: contact resistance and resistance inherent in the spheroid structure. Mechanisms of MCR include: inhibition of apoptosis, high proportion of quiescent cells, modulation of protein expression (including topoisomerases and repair enzymes), potential permeability problems, presence of a hypoxic and necrotic centre and other possible mechanisms that remain to be discovered. A new therapeutic class of drugs is required to overcome MCR. Compounds, which are able to disrupt communication and binding between tumour cells and their microenvironment, seem to be able to circumvent MCR. Interesting results are obtained in vitro and in vivo in mice with specific antibodies or peptides recognised by cell binding proteins. Interestingly, these compounds also appear to be able to inhibit metastasis. Hyaluronidase has already been used with anticancer drugs in patients and was shown to increase drug potency. The explanation given is that it improves drug penetration into spheroids. We now hypothesise that hyaluronidase, in fact, decreases MCR and thus could be the first member of a new therapeutic class.     

Lack of aspirin effect: aspirin resistance or resistance to taking aspirin?

Background

A lack of aspirin effect on platelets after a myocardial infarction (MI) is associated with poor health outcome. This lack of effect may be due to biological resistance to aspirin or due to nonadherence (the patient is not taking the aspirin, hence it has no effect). Determining which of these factors predicts poor outcome would inform potential intervention strategies.

Methods

Aspirin effect on platelets was assessed in a cohort of MI survivors who were divided into three groups: group A (“adherent”), patients whose platelets were affected by aspirin; group B (“nonadherent”), patients whose platelets showed no aspirin effect and who admitted in an interview that they were not taking their medications; and group C (potentially biologically resistant to aspirin), patients whose platelets showed no aspirin effect but maintained that they were taking their aspirin. Two health outcome measures (death, reinfarction, or rehospitalization for unstable angina; or admission for any cardiovascular causes) were assessed 12 months after enrollment.

Results

Seventy-three patients were enrolled and classified into groups A (“adherent,” 52 patients), B (“nonadherent,” 12 patients), and C (“potentially aspirin resistant,” 9 patients). Adverse events and readmission were more common in the nonadherent group (B)—42% and 67%, respectively, when compared with the adherent group (A)—6% and 11%, and with the potentially biologically resistant group (C)—11% and 11%.

Conclusions

Nonadherence is a significant mediator of poor outcome. It is important to evaluate whether or not patients are taking their medications in clinical settings and in studies that evaluate the effect of prescribed medications.     

Antimicrobial resistance—Pharmacological solutions

The interaction between microbial resistance and antibacterial agents occurs in a direct and an indirect fashion. Directly—through the development of resistance to the agent used, or to agents of the same class—as exemplified by the induction of β-lactamase by both grampositive and gram-negative bacteria. It also takes place through the development of resistance to compounds of different classes to the compound used, as exemplified by the loss ofStreptococcus pneumoniae susceptibility to penicillin that is accompanied by a parallel loss of sensitivity to erythromycin and to tetracycline. As for the indirect way—microbial resistance may develop through selection of resistant organisms when the patient is treated with antibiotics, when the environment is contaminated with antibiotics (hospital) or when antibacterial agents are used in agriculture and animal husbandry.     

Aspirin resistance: fact or fiction?

A meta-analysis of clinical studies of patients with cardiovascular disease demonstrated that the use of aspirin was associated with a 22% decrease in death rates and relevant ischemic vascular events. However, clinical studies demonstrated that patients that regularly took aspirin presented recurrence of cardiovascular events. Such observation led to the question whether, in some patients, the aspirin was not effective in blocking platelet aggregation and these patients were called unresponsive to aspirin or aspirin-resistant. The clinical aspirin resistance is characterized as the occurrence of cardiovascular events in patients during treatment with aspirin, whereas the laboratory resistance is defined as the persistence of platelet aggregation, documented by laboratory test, in patients regularly taking aspirin. Patients that are aspirin-resistant presented, according to laboratory tests, on average 3.8 times more cardiovascular events when compared to non-resistant ones.     

Aspirin resistance: does it exist?

Aspirin irreversibly inhibits platelet cyclooxygenase-1 (COX-1). Aspirin sensitivity can be measured easily by its inhibition of arachidonic acid (AA) -induced platelet aggregation. Aspirin resistance has to be defined by its inability to inhibit COX-1. By using this definition, aspirin resistance very likely does not exist. A specific rapid laboratory test using either AA-induced platelet aggregation or AA-induced malondialdehyde production in platelet-rich plasma is needed to test aspirin sensitivity. The reports on so-called aspirin resistance are usually due to noncompliance of aspirin intake or consumption of inadequate doses of aspirin. In addition, data generated from using nonspecific platelet function tests have added confusion to this observed phenomenon of aspirin resistance.     

Wide clinical implementation of insulin resistance syndrome?

The aim of this paper is to review the literature regarding the metabolic syndrome and the single factor that links all its core components. That single factor seems to be partial insulin deficiency (PID), which is responsible for varying degrees of atherosclerotic vascular damage. In conclusion, we found that the diagnosis of insulin resistance syndrome (IRS) may allow clinicians to diagnose and treat atherosclerosis at an early stage-to stop or reverse vascular damage.