Helga van Rennes

Response of the clinically uninvolved skin of psoriatic patients to standardized injury.

Test sites on healthy controls and on the clinically uninvolved skin of psoriatic patients were stripped with tape, and eight variables were quantified at intervals during the subsequent healing process.

Metabolic changes at the margin of the spreading psoriatic lesion

Keratotome slices were cut across the margins of rapidly‐spreading psoriatic plaques. Each slice was divided into eight sections and in each section we measured the percentage cells in S phase and the levels of glucose‐6‐phosphate dehydrogenase (both related to epidermal proliferation), acid phosphatase (associated with keratinization) and alkaline phosphatase (a marker for dermal capillaries).

In vivo antitumor activity of sparsomycin and its analogues in eight murine tumor models.

SummarySparsomycin (Sm) is a known inhibitor of ribosomal protein synthesis with an attractive anticancer potential. Recently, several analogues of Sm which are more active than the parent drug were selected for further study on the basis of in vitro investigations. Six analogues as well as the parent drug were tested for their antitumor activity in eight in vivo murine tumor models: P388 and L1210 leukemias, RC renal cell carcinoma, B16 melanoma, C38 colon carcinoma, LL Lewis lung carcinoma, C22LR osteosarcoma and M5076 sarcoma. Sm itself appeared to have only borderline activity on L1210 leukemia. The analogues that were most active in vitro showed also the highest in vivo activity. The most sensitive tumors were RC, L1210 and P388. Minimal activity was found on B16 and no activity on C22LR, M5076, C38 and LL. The most active compounds are deshydroxy-Sm, ethyl-deshydroxy-Sm and n-pentyl-Sm. There was a considerable loss of activity when L1210 leukemia was implanted sc while the drugs were administered iv. Only one drug, ethyl-deshydroxy-Sm appeared to be active in this assay. No single most effective compound could be found in this study. The overall activity of Sm and its analogues is moderate. The three analogues which show high activity in three ascitic tumors will be further investigated using human tumor xenograft models.

Cutaneous alkaline phosphatase: A biochemical study

SummaryA fluorometric microassay of alkaline phosphatase is described; it is based on the hydrolysis of 4-methylumbelliferyl phosphate and is about three orders of magnitude more sensitive than the usual colorimetric procedures. When applied to skin, the addition of fluoride is necessary to avoid interference from the relatively high levels of acid phosphatase present in the epidermis.Kinetic data for cutaneous alkaline phosphatase are reported. Skin appears to contain a single enzyme of the ‘bone-liver-kidney’ type, which is present both in a soluble and in membrane-bound form. It occurs almost exclusively in the dermis, not more than 1% of the total alkaline phosphatase of human skin being present in the epidermis.

In vivo potentiation of cis-diamminedichloroplatinum (II) antitumor activity by pretreatment with sparsomycin

The influence of protein synthesis inhibition by sparsomycin (Sm) on in vivo cisplatin activity has been studied on BALBc X DBA2: F1 mice bearing L1210 leukemia i.p. Sm alone at the dose range from 0.5 to 3.0 mg/kg did not significantly improve animal survival. Sm potentiated cisplatin activity only when given 3 or 6 h prior to cisplatin (P less than 0.001). Sm 0.5-1.5 mg/kg 3 h prior to cisplatin resulted in a significant prolongation of animal survival (P less than 0.001) and 66% cures in each group versus 0% due to cisplatin alone. Sm pretreatment decreased weight loss due to cisplatin suggesting that it probably is able to decrease cisplatin toxicity.

Pharmacokinetics and toxicology of sparsomycin in beagle dogs

SummarySparsomycin is a cytotoxic drug exhibiting a broad spectrum of in vitro activity against murine tumors and many tumor cell lines. It also appears to be a potent stimulator of the antitumor activity of cisplatin against L1210 leukemia in vivo. However, because of its toxicity, the antitumor activity of sparsomycin on murine tumors in vivo has been disappointing. The purpose of our study was to investigate the pharmacokinetics of this drug as well as the possible mechanisms that produce sparsomycin toxicity. Tests on beagle dogs revealed that about 60% of the drug is eliminated by metabolic clearance, while 40% is eliminated by the kidneys. After a single bolus injection of 0.1 mg/kg sparsomycin without narcosis, sparsomycin was eliminated with a tβ1/2 of 0.6–0.7 h, the AUC being 0.32–0.38 mg·h·1-1, and the volume of distribution (Vd) 0.26 l/kg. In addition to being subject to glomerular filtration, sparsomycin is probably also actively excreted and actively reabsorbed by the renal tubuli. Sparsomycin itself may inhibit its active tubular excretion, thus resulting in a decrease in the drugs renal clearance and its accumulation in the plasma. Sparsomycin appeared to be toxic primarily in the liver, disturbing its function and the synthesis of plasma proteins. Two out of five dogs developed hemorrhagic diathesis due to hypofibrinogenemia and deficiency of other blood-coagulation factors. Sparsomycin was not toxic to the bone marrow.

Metabolic changes in the psoriatic lesion during therapy

Three marker enzymes were measured during treatment of psoriatic plaques with two different therapies. During treatment with clobetasol propionate the epidermal enzymes (acid phosphatase and glucose‐6‐phosphate dehydrogenase) returned to normal within 14 days whereas capillary alkaline phosphatase remained at the original level. By contrast, all three marker enzymes reverted to normal at the same tempo during PUVA therapy, reaching the control range after 4–8 weeks.

Alpha-l-fucosidase in normal and psoriatic epidermis.

Alpha‐L‐fucosidase levels in psoriatic epidermis rule out the concept of a primary defect of this enzyme in psoriasis.