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Clin Cancer Res. 1999 Feb;5(2):267-74.
Persistent induction of apoptosis and suppression of mitosis as the basis for curative therapy with S-1, an oral 5-fluorouracil prodrug in a colorectal tumor model.

Cao S, Lu K, Toth K, Slocum HK, Shirasaka T, Rustum YM.

Department of Pharmacology and Therapeutics, Grace Cancer Drug Center, Roswell Park Cancer Institute, Buffalo, New York 14263-0001, USA. scac3101.med.buffalo.edu

In an effort to improve the therapeutic selectivity of 5-fluorouracil (FUra) against colorectal cancer, S-1, a combination agent including a prodrug of FUra with two modulators, was recently developed by Taiho Pharmaceuticals Co. S-1 is a combination of tegafur (FT), 5-chloro-2,4-hydroxypyridine, and potassium oxonate in the molar ratio of 1.0:0.4:1.0, with the latter two components as inhibitors of dihydropyrimidine dehydrogenase and phosphoribosylpyrophosphate transferase, respectively. In this study, the therapeutic selectivity and efficacy of S-1 (oral) was compared with FT (oral) and FUra (i.v. infusion) in rats bearing advanced colorectal cancer by using clinically relevant schedules. The maximum tolerated doses (MTDs) of S-1, FT, and FUra were 31.5, 200, and 25 mg/kg/d for 7 days and 22.5, 150, and 12.5 mg/kg/d for 28 days, respectively. The therapeutic index of S-1 was 4- to 5-fold higher than that of either FT or FUra. S-1 achieved 100% complete tumor regression (CR) at its MTD in both 7-day and 28-day schedules. Furthermore, the high incidences of stomatitis, alopecia, and diarrhea observed with FUra and FT, were not observed with S-1. In an attempt to understand the basis for the observed superior therapeutic selectivity with S-1, we studied pharmacokinetic analysis of FUra, drug-induced apoptosis, suppression of mitosis, and inhibition of thymidylate synthase (TS) after S-1, FUra, or FT administration. The peak plasma FUra concentrations derived from FUra or S-1 (FT) at comparable MTDs were similar, but the plasma level of FUra was higher with S-1 than with FUra. Induction of high and sustained apoptosis was achieved with S-1. Although the initial level of apoptosis induced by FUra was comparable to S-1, it was not sustained. The sustained level of apoptosis appears to correlate with tumor growth inhibition. Mitotic figures were more greatly suppressed with S-1 treatment than with FUra. Studies on TS inhibition indicated that, although both S-1 and FUra caused a 4- to 6-fold induction of total TS protein, single oral administration of S-1 was superior to 24-h infusion of FUra in suppressing free TS. The data are consistent with the observation that the therapeutic efficacy of S-1 (100% cure) over FUra is associated with high and sustained levels of drug-induced apoptosis, greater suppression of mitosis, and inhibition of free TS in tumor tissues.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10037174&dopt=Abstract

Pediatr Dermatol. 1999 Jan-Feb;16(1):6-11.
A prospective survey of pediatric dermatology clinic patients in Kuwait: an analysis of 10,000 cases.

Nanda A, Al-Hasawi F, Alsaleh QA.

Department of Dermatology, Asad' Al-Hammad Dermatology Center, Al-Sabah Hospital, Kuwait.

Skin diseases are common in children. However, only a very few prospective epidemiologic surveys are available in the literature. The present survey was directed at determining the spectrum and pattern of skin diseases of children in Kuwait. A total of 10,000 consecutive new patients were studied; 96% were children of Arab descent. A female preponderance (52%) was observed, and infants constituted the largest group within the patient population (28.7%). A total of 162 dermatoses were recorded. Atopic dermatitis was the most prevalent dermatosis (31.3%), followed by viral warts (13.1%), alopecia areata (6.7%), pityriasis alba (5.25%), psoriasis (4%), and diaper dermatitis (4%). Atopic dermatitis was the most frequently seen dermatosis in children of all age groups, whereas, viral warts were more prevalent in school-age children. The prevalence of alopecia areata and psoriasis was higher than reported earlier in other ethnic groups. A female preponderance was seen in children with alopecia areata, psoriasis, vitiligo, acne vulgaris, contact dermatitis, and pityriasis rosea. Dermatitis, superficial cutaneous infections, and nevi/nevoid disorders were the important groups studied.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10027990&dopt=Abstract

Am J Dermatopathol. 1999 Feb;21(1):46-50.
Diffuse alopecia with stem cell folliculitis: chronic diffuse alopecia areata or a distinct entity?

Kossard S.

Skin and Cancer Foundation, Darlinghurst, NSW, Australia.

A 34-year-old woman presented with an 8-year history of slowly progressive diffuse nonscarring alopecia with loss of hair density. Scalp biopsy specimens showed increased miniaturized follicles and an asymmetric wedge-shaped lymphocytic infiltrate concentrated on the stem cell-rich region at the point of entry of sebaceous ducts and at bulge-like regions of multiple follicles. Several hair bulbs emerging at the stem cell compartment also were inflamed, but the hair bulbs in the deeper dermis and subcutis were spared. I speculate whether these findings may represent a stem cell folliculitis similar to the reaction pattern previously observed in graft versus host disease and in androgenetic alopecia. The additional presence of peribulbar lymphocytic inflammation could indicate that the patient had a variant of alopecia areata. The clinical presentation of a slowly progressive diffuse alopecia without progression to clinically recognizable alopecia areata and the prominent lymphocytic inflammation involving the stem cell compartment may prompt a reexamination of similar cases currently classified as chronic diffuse alopecia areata. The concept that lymphocytes can inhibit stem cell function without destroying the stem cells themselves needs consideration.

online pharmacy ref. source: www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=10027527&dopt=Abstract

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