Lip hypertrophy secondary to cyclosporine treatment: a rare adverse effect and treatment considerations.

Gingival hypertrophy is a well-known and extensively documented undesirable side effect of cyclosporine in posttransplant patients. However, severe lip enlargement associated with cyclosporine is less recognized and has seldom been reported in the literature. Lip enlargement may lead to social, physical, and psychological stress, especially in the older childhood and adolescent age groups. We present a case of marked lip hypertrophy and concomitant gingival hypertrophy secondary to cyclosporine (Neoral) treatment in a pediatric bilateral lung transplant recipient. We also discuss the various side effects and treatment considerations available including more recent substitution therapy. Cyclosporine has most effectively and conclusively enabled transplantation of solid organs by reducing transplant-associated morbidity. We believe clinicians should be knowledgeable and aware of lip hypertrophy associated with cyclosporine use. This rare and less understood adverse effect should be recognized during the clinical evaluation of the posttransplant patient.

Gamma-tocopheryl quinone stimulates apoptosis in drug-sensitive and multidrug-resistant cancer cells.

Chemotherapy-induced cell death is linked to apoptosis, and there is increasing evidence that multidrug-resistance in cancer cells may be the result of a decrease in the ability of a cell to initiate apoptosis in response to cytotoxic agents. In previous studies, we synthesized two classes of electrophilic tocopheryl quinones (TQ), nonarylating alpha-TQ and arylating gamma- and delta-TQ, and found that gamma- and delta-TQ, but not alpha-TQ, were highly cytotoxic in human acute lymphoblastic leukemia cells (CEM) and multidrug-resistant (MDR) CEM/VLB100. We have now extended these studies on tumor biology with CEM, HL60 and MDR HL60/MX2 human promyelocytic leukemia, U937 human monocytic leukemia, and ZR-75-1 breast adenocarcinoma cells. gamma-TQ, but not alpha-TQ or tocopherols, showed concentration and incubation time-dependent effects on loss of plasma membrane integrity, diminished viable cell number, and stimulation of apoptosis. Its cytotoxicity exceeded that of doxorubicin in HL60/MX2 cells, which express MRP, an MDR-associated protein. Apoptosis was confirmed by TEM, TUNEL, and DNA gel electrophoresis. Kinetic studies showed that an induction period was required to initiate an irreversible multiphase process. Gamma-TQ released mitochondrial cytochrome c to the cytosol, induced the cleavage of poly(ADP-ribose)polymerase, and depleted intracellular glutathione. Unlike xenobiotic electrophiles, gamma-TQ is a highly cytotoxic arylating electrophile that stimulates apoptosis in several cancer cell lines including cells that express MDR through both P-glycoprotein and MRP-associated proteins. The biological properties of arylating TQ electrophiles are closely associated with cytotoxicity and may contribute to other biological effects of these highly active agents.