title: Cellular and organismal toxicity of the anti-cancer small molecule, tolfenamic acid: a pre-clinical evaluation.
abstract: OBJECTIVE
  The small molecule, Tolfenamic acid (TA) has shown anti-cancer activity in pre-clinical models and is currently in Phase I clinical trials at MD Anderson Cancer Center Orlando. Since specificity and toxicity are major concerns for investigational agents, we tested the effect of TA on specific targets, and assessed the cellular and organismal toxicity representing pre-clinical studies in cancer.
  
  
  METHODS
  Panc1, L3.6pl, and MiaPaCa-2 (pancreatic cancer), hTERT-HPNE(normal), and differentiated/un-differentiated SH-SY5Y (neuroblastoma) cells were treated with increasing concentrations of TA. Cell viability and effect on specific molecular targets, Sp1 and survivin were determined. Athymic nude mice were treated with vehicle or TA (50mg/kg, 3times/week for 6 weeks) and alterations in the growth pattern, hematocrit, and histopathology of gut, liver, and stomach were monitored.
  
  
  RESULTS
  TA treatment decreased cell proliferation and inhibited the expression of Sp1 and survivin in cancer cells while only subtle response was observed in normal (hTERT-HPNE) and differentiated SH-SY5Y cells. Mice studies revealed no effect on body weight and hematocrit. Furthermore, TA regimen did not cause signs of internal-bleeding or damage to vital tissues in mice.
  
  
  CONCLUSIONS
  These results demonstrate that TA selectively inhibits malignant cell growth acting on specific targets and its chronic treatment did not cause apparent toxicity in nude mice.
authors.affiliation: Cancer Research Institute, MD Anderson Cancer Center Orlando, Orlando FL, USA.
authors.forename: Umesh T
authors.initials: UT
authors.lastname: Sankpal
authors.forename: Chris M
authors.initials: CM
authors.lastname: Lee
authors.forename: Sarah F
authors.initials: SF
authors.lastname: Connelly
authors.forename: Omer
authors.initials: O
authors.lastname: Kayaleh
authors.forename: Don
authors.initials: D
authors.lastname: Eslin
authors.forename: Robert
authors.initials: R
authors.lastname: Sutphin
authors.forename: Steven
authors.initials: S
authors.lastname: Goodison
authors.forename: Lina
authors.initials: L
authors.lastname: Adwan
authors.forename: Nasser H
authors.initials: NH
authors.lastname: Zawia
authors.forename: Lenard M
authors.initials: LM
authors.lastname: Lichtenberger
authors.forename: Riyaz
authors.initials: R
authors.lastname: Basha
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D001835:Body Weight / Q000187:drug effects*; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D004353:Drug Evaluation, Preclinical; D006400:Hematocrit; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D007422:Intestines / Q000473:pathology; D008099:Liver / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D012097:Repressor Proteins / Q000378:metabolism; D016329:Sp1 Transcription Factor / Q000378:metabolism; D013270:Stomach / Q000473:pathology; D000077022:Survivin; D062367:ortho-Aminobenzoates / Q000633:toxicity*
chemical_list: D000970:Antineoplastic Agents; C117749:Birc5 protein, mouse; D051034:Inhibitor of Apoptosis Proteins; D012097:Repressor Proteins; D016329:Sp1 Transcription Factor; D000077022:Survivin; D062367:ortho-Aminobenzoates; C009500:tolfenamic acid