PMID- 16133793
OWN - NLM
STAT- MEDLINE
DCOM- 20060302
LR  - 20220317
IS  - 0167-6997 (Print)
IS  - 0167-6997 (Linking)
VI  - 23
IP  - 5
DP  - 2005 Oct
TI  - Flexible heteroarotinoids (Flex-Hets) exhibit improved therapeutic ratios as 
      anti-cancer agents over retinoic acid receptor agonists.
PG  - 417-28
AB  - The anti-cancer activities and toxicities of retinoic acid (RA) and synthetic 
      retinoids are mediated through nuclear RA receptors (RARs) and retinoid X 
      receptors (RXRs) that act as transcription factors. Heteroarotinoids (Hets), 
      which contain a heteroatom in the cyclic ring of an arotinoid structure, exhibit 
      similar anti-cancer activities, but reduced toxicity in vivo, in comparison to 
      parent retinoids and RA. A new class of Flexible Hets (Flex-Hets), which contain 
      3-atom urea or thiourea linkers, regulate growth and differentiation similar to 
      RA, but do not activate RARs or RXRs. In addition, Flex-Hets induce potent 
      apoptosis in ovarian cancer and in head and neck cancer cell lines through the 
      intrinsic mitochondrial pathway. In this study, 4 cervical cancer cell lines were 
      growth inhibited by micromolar concentrations of Flex-Hets to greater extents 
      than RAR/RXR active retinoids. The most potent Flex-Het (SHetA2) inhibited each 
      cell line of the National Cancer Institute's human tumor cell line panel at 
      micromolar concentrations. Oral administration of Flex-Hets (SHetA2 and SHetA4) 
      inhibited growth of OVCAR-3 ovarian cancer xenografts to similar extents as 
      administration of a RAR/RXR-panagonist (SHet50) and Fenretinide (4-HPR) in vivo. 
      None of these compounds induced evidence of skin, bone or liver toxicity, or 
      increased levels of serum alanine aminotransferase (ALT) in the treated mice. 
      Topical application of Flex-Hets did not induce skin irritation in vivo, whereas 
      a RAR/RXR-panagonist (NHet17) and a RARgamma-selective agonist (SHet65) induced 
      similar irritancy as RA. In conclusion, Flex-Hets exhibit improved therapeutic 
      ratios for multiple cancer types over RAR and/or RXR agonists.
FAU - Benbrook, Doris M
AU  - Benbrook DM
AD  - Departments of Obstetrics and Gynecology, University of Oklahoma Health Sciences 
      Center, Oklahoma City, OK 73190, USA. Doris-Benbrook@ouhsc.edu
FAU - Kamelle, Scott A
AU  - Kamelle SA
FAU - Guruswamy, Suresh B
AU  - Guruswamy SB
FAU - Lightfoot, Stan A
AU  - Lightfoot SA
FAU - Rutledge, Teresa L
AU  - Rutledge TL
FAU - Gould, Natalie S
AU  - Gould NS
FAU - Hannafon, Bethany N
AU  - Hannafon BN
FAU - Dunn, S Terence
AU  - Dunn ST
FAU - Berlin, K Darrell
AU  - Berlin KD
LA  - eng
GR  - CA73639/CA/NCI NIH HHS/United States
GR  - CA7771/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, P.H.S.
PL  - United States
TA  - Invest New Drugs
JT  - Investigational new drugs
JID - 8309330
RN  - 0 ((((4-(ethoxycarbonyl)phenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) 
      methan-1-one)
RN  - 0 ((((4-(ethoxycarbonyl)phenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) 
      methane-1-thione)
RN  - 0 ((((4-nitrophenyl)amino)(2,2,4,4-tetramethyl thiochroman-6-yl)amino) 
      methane-1-thione)
RN  - 0 (Antineoplastic Agents)
RN  - 0 (Chromans)
RN  - 0 (Phenylurea Compounds)
RN  - 0 (Receptors, Retinoic Acid)
RN  - 0 (Retinoid X Receptors)
RN  - 0 (Thiones)
RN  - 63231-63-0 (RNA)
RN  - EC 2.6.1.2 (Alanine Transaminase)
RN  - GYV9AM2QAG (Thiourea)
SB  - IM
MH  - Alanine Transaminase/blood
MH  - Animals
MH  - Antineoplastic Agents/*pharmacology
MH  - Apoptosis
MH  - Cell Differentiation/drug effects
MH  - Cell Line, Tumor
MH  - Cell Proliferation/drug effects
MH  - Chromans/*pharmacology
MH  - Female
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Humans
MH  - Mice
MH  - Mice, Inbred Strains
MH  - Ovarian Neoplasms/drug therapy
MH  - Phenylurea Compounds/*pharmacology
MH  - RNA/metabolism
MH  - Receptors, Retinoic Acid/agonists/genetics/metabolism
MH  - Retinoid X Receptors/agonists/genetics/metabolism
MH  - Skin Irritancy Tests
MH  - Thiones/*pharmacology
MH  - Thiourea/*analogs & derivatives/pharmacology
MH  - Uterine Cervical Neoplasms/drug therapy/genetics/metabolism
MH  - Xenograft Model Antitumor Assays
EDAT- 2005/09/01 09:00
MHDA- 2006/03/03 09:00
CRDT- 2005/09/01 09:00
PHST- 2005/09/01 09:00 [pubmed]
PHST- 2006/03/03 09:00 [medline]
PHST- 2005/09/01 09:00 [entrez]
AID - 10.1007/s10637-005-2901-5 [doi]
PST - ppublish
SO  - Invest New Drugs. 2005 Oct;23(5):417-28. doi: 10.1007/s10637-005-2901-5.