LAV694, a new antiproliferative agent showing improved skin tolerability vs. clinical standards for the treatment of actinic keratosis.
The skin tolerability of the tubulin polymerisation inhibitor LAV694 was compared to that of 5% 5-fluorouracil (5-FU) and 0.5% podophyllotoxin in vitro using a human reconstructed epidermis (HRE), and in vivo using minipigs. Topical treatment of HRE for 1 or 3 days with a 0.2, 0.6 or 1% LAV694 cream or the placebo showed no signs of irritation in terms of morphology, cell viability (lactate dehydrogenase leakage) or interleukin-8 mRNA expression and release. 5-FU increased interleukin-8 production and induced morphological signs of irritation. The substances were also applied under occlusion to the back of two minipigs, twice daily, for 9 days to allow intraindividual comparison of skin effects and tolerability. Skin reactions were monitored by visual scoring, chromometry, pro-inflammatory activity, cell cycle and apoptosis by RT-PCR, laser scanning cytometry and histopathological examination of biopsies. Application of podophyllotoxin and 5-FU had to be stopped on days 4 and 8, respectively, due to severe skin lesions. LAV694 (1%) induced only moderate skin reddening after 9 days. 5-FU and podophyllotoxin, but not LAV694, increased mRNA expression of pro-inflammatory cytokines. LAV694 arrested keratinocytes in the M phase of the cell cycle and apoptosis was detected histologically in the basal layer. LAV694 increased the expression of pro-apoptotic genes in both experimental models. In conclusion, LAV694 selectively induced apoptosis, rather than necrosis, of growth-arrested keratinocytes, thus avoiding the occurrence of extensive inflammation. This resulted in an improved skin tolerability in comparison with 5-FU and podophyllotoxin.
Preclinical Safety Department, Novartis Pharma AG, WSH.2881.P03, CH-4002 Basel, Switzerland.
Jesús
J
Medina
Valérie
V
Picarles
Brigitte
B
Greiner
Christian
C
Elsaesser
Maryelle
M
Kolopp
Andreas
A
Mahl
Danielle
D
Roman
Beate
B
Vogel
Peter
P
Nussbaumer
Anthony
A
Winiski
Josef
J
Meingassner
Anne de Brugerolle de
Ade B
Fraissinette
D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects; D004195:Disease Models, Animal; D004361:Drug Tolerance; D006801:Humans; D015603:Keratinocytes / Q000187:drug effects; D007642:Keratosis / Q000188:drug therapy*; D010636:Phenols / Q000009:adverse effects / Q000627:therapeutic use*; D012871:Skin Diseases / Q000139:chemically induced; D013552:Swine
D000970:Antineoplastic Agents; C479762:LAV694; D010636:Phenols