Antitumor activity of 3-ingenyl angelate: plasma membrane and mitochondrial disruption and necrotic cell death.

Options for skin cancer treatment currently include surgery, radiotherapy, topical chemotherapy, cryosurgery, curettage, and electrodessication. Although effective, surgery is costly and unsuitable for certain patients. Radiotherapy can leave a poor cosmetic effect, and current chemotherapy is limited by low cure rates and extended treatment schedules. Here, we describe the preclinical activity of a novel topical chemotherapeutic agent for the treatment of skin cancer, 3-ingenyl angelate (PEP005), a hydrophobic diterpene ester isolated from the plant Euphorbia peplus. Three daily topical applications of 42 nmol (18 micro g) of PEP005 cured a series of s.c. mouse tumors (B16 melanoma, LK2 UV-induced squamous cell carcinoma, and Lewis lung carcinoma; n = >14 tumors/group) and human tumors (DO4 melanoma, HeLa cervical carcinoma, and PC3 and DU145 prostate carcinoma; n = >4 tumors/group) previously established (5-10 mm(3)) on C57BL/6 or Foxn1(nu) mice. The treatment produced a mild, short-term erythema and eschar formation but, ultimately, resulted in excellent skin cosmesis. The LD(90) for PEP005 for a panel of tumor cell lines was 180-220 micro M. Electron microscopy showed that treatment with PEP005 both in vitro (230 micro M) and in vivo (42 nmol) rapidly caused swelling of mitochondria and cell death by primary necrosis. (51)Cr release, uptake of propidium iodide, and staining with the mitochondria dye JC1, revealed that PEP005 (230 micro M) treatment of tumor cells in vitro resulted in a rapid plasma membrane perturbation and loss of mitochondrial membrane potential. PEP005 thus emerges as a new topical anti-skin cancer agent that has a novel mode of action involving plasma membrane and mitochondrial disruption and primary necrosis, ultimately resulting in an excellent cosmetic outcome.

A longitudinal perspective on neurodevelopmental outcome after infant cardiac transplantation.

BACKGROUND: With improvement in medical outcomes, the current research has shifted toward understanding and enhancing the quality of life after pediatric heart transplantation. Previous research has indicated that infant heart transplant recipients are generally at risk for neurodevelopmental delays; however, no longitudinal studies exploring the patterns of development within this medical population have been performed. METHODS: Using the Bayley Scales of Infant Development-II, 39 children (2 to 38 months of age) who underwent heart transplantation in infancy (<1 year) at Loma Linda University Children's Hospital were assessed consecutively over time. RESULTS: Mean Mental Development Index (MDI) scores for all age groups were within normal limits, except for the age ranges of 18 to 23 and 24 to 35 months, which were mildly delayed. Average Psychomoter Development Index (PDI) scores for all age groups reflected mildly delayed performance, except for the 36- to 38-month age group, which was within normal limits. Repeated measures analyses of variance on a sub-set of participants with at least 4 consecutive assessments revealed within-subject effects on MDI scores (F = 5.7, p < 0.01), but not on PDI scores (F = 1.6, p = 0.22). Significant decreases in MDI scores at 18 and 28 to 36 months were noted. CONCLUSIONS: Motor development in this population was consistently mildly delayed. Age-dependent variability in cognitive skills was apparent. The delays appeared due to speech/language acquisition (18 months), and abstract reasoning/goal-directed behaviors (28 to 36 months). Possible etiologies for cognitive delays include test artifacts, auditory functioning and effects of immunosuppressive agents. Understanding risk factors in this patient population will allow for early and effective intervention.