The role of signal transduction in cancer treatment and drug resistance.

Drug resistance in the treatment of cancer still remains a major clinical challenge, in part due to an insufficient understanding of the pathways by which these drugs interact with the mechanisms underlying cellular behaviour and cancer pathogenesis. Signal transduction involves cell differentiation, proliferation and cell death with alterations in these mechanisms being involved in the pathogenesis of cancer. It has been postulated that such pathways could be linked to anti-cancer drug resistance. Recently, novel approaches to overcome anti-cancer drug resistance through manipulation of signal transduction pathways, have been introduced in clinical trials. In this article we present a review of the current understanding in the field of signal transduction and the existing evidence for its role in drug resistance. We also discuss its clinical relevance with regard to overcoming drug resistance.

Oxypentifylline in the management of recurrent aphthous oral ulcers: an open clinical trial.

OBJECTIVE: The purpose of this study was to determine the efficacy of oxypentifylline in the treatment of recurrent oral aphthous ulcers and to compare the results with those of previous studies. STUDY DESIGN: A 6-week open trial and a patient survey regarding pain were conducted at the Oral and Maxillofacial Surgery Unit, City General Hospital, Carlisle. Twenty-four patients (11 male and 13 female) were selected from sequential referrals involving complaints of recurrent oral ulcers. A 2-week pretrial period was used to record data pertaining to the occurrence, duration, and pain associated with ulcers. A 4-week period of treatment with oxypentifylline (400 mg administered orally 3 times daily) was followed by an assessment of improvement at the end of 6 weeks. RESULTS: The results were comparable to those of previous studies, with positive responses seen in 63.6% of male patients and 61.5% of female patients. However, recurrence of ulcers was noted in all patients once the drug was discontinued. This was attributed to the small size of the patient sample studied and to the relatively short duration of treatment. No significant side effects were noted. CONCLUSIONS: Double-blind, controlled studies are indicated for a definitive assessment of the efficacy of oxypentifylline in the management of recurrent oral aphthous ulcers. The encouraging results of this study support the suggestion that the use of oxypentifylline be considered in refractory cases of recurrent oral aphthous ulcers.

Severity score for predicting pneumonia in inhalation injury patients.

Inhalation injuries contribute significantly to morbidity and mortality in both children and adults with burns. Pneumonia is a major compromising factor in these patients. The purpose of this article was to evaluate the characteristics, impact factors, incidence, morbidity, and mortality of pneumonia in inhalation injuries. Furthermore, a severity score has been formulated to help predict the probability of developing pneumonia following inhalation injuries. A retrospective study was performed of 214 patients, treated for inhalation injuries from 1999 to 2009 at the Burn Center in Chang Gung Memorial Hospital, Linkou, Taiwan. Patients' characteristics, length of hospitalization, total burn surface area, initial PaO2:FiO2 ratio, number of intubated days, bronchoscope grade, initial carboxyhemoglobin level (COHb) and mortality rate were recorded. A Student's t-test was used for comparison of inhalation injury patients with and without pneumonia and was also used for comparing a TBSA of >20% to those with a TBSA of ≤20% in patients with inhalation injury and pneumonia. Logistic regression analyses were utilized to create a severity score related to pneumonia. 129 patients with inhalation injury were included in the analysis. Overall, 38% (49/129) patients developed pneumonia. Pneumonia associated with inhalation injury occurred more often in patients with a TBSA>20% (P<0.05). The intubation days, bronchoscope grade and COHb level of pneumonia patients were significantly longer (P<0.05). Initial PaO2:FiO2 ratio (PaO2/FiO2) was significantly lower in patients with pneumonia (P<0.05). Mortality following pneumonia was increased sevenfold (P<0.05). Hospitalization days and intubation days were significantly longer in TBSA>20%. Logistic regression analysis was performed to find out the impact factors of pneumonia in inhalation injury patients and to set a severity score. Patients age >60 years, TBSA >20%, bronchoscope grade is 3 or 4, initial PaO2/FiO2≦300 and initial COHb level>10% showed a significant difference (P<0.05). The total severity scale was set at 5 points. Each impact factor was given one point and when the score ≥2 it means patients have high risk of development of pneumonia. This study had identified the significant risk factors for potential development of pneumonia in a group of inhalation injury patients. The impact of these risk factors should be validated in further prospective trials to improve outcome or at least reduce the incidence of the surrogate diagnosis of pneumonia.

Doxorubicin and vinorelbine act independently via p53 expression and p38 activation respectively in breast cancer cell lines.

In the treatment of breast cancer, combination chemotherapy is used to overcome drug resistance. Combining doxorubicin and vinorelbine in the treatment of patients with metastatic breast cancer has shown high response rates; even single-agent vinorelbine in patients previously exposed to anthracyclines results in significant remission. Alterations in protein kinase-mediated signal transduction and p53 mutations may play a role in drug resistance with cross-talk between signal transduction and p53 pathways. The aim of this study was to establish the effects of doxorubicin and vinorelbine, as single agents, in combination, and as sequential treatments, on signal transduction and p53 in the breast cancer cell lines MCF-7 and MDA-MB-468. In both cell lines, increased p38 activity was demonstrated following vinorelbine but not doxorubicin treatment, whether vinorelbine was given prior to or simultaneously with doxorubicin. Mitogen-activated protein kinase (MAPK) activity and p53 expression remained unchanged following vinorelbine treatment. Doxorubicin treatment resulted in increased p53 expression, without changes in MAPK or p38 activity. These findings suggest that the effect of doxorubicin and vinorelbine used in combination may be achieved at least in part through distinct mechanisms. This additivism, where doxorubicin acts via p53 expression and vinorelbine through p38 activation, may contribute to the high clinical response rate when the two drugs are used together in the treatment of breast cancer.