Effects of N1, N13-diethylnorspermine (DENSPM) and X-radiation treatment on human colorectal tumor clones with varying X-radiation and drug responses.
This study was designed to examine the effects of treatment with N1, N13-diethylnorspermine (DENSPM), a spermine analog, and X radiation on survival and on the polyamine and spermidine/spermine N1-acetyltransferase (SSAT) levels in closely related human colorectal tumor (HCT116) clones exhibiting a wide range of X-radiation and drug responses. After treatment with DENSPM and X radiation, clonogenic cell survival was measured. SSAT protein levels were measured by Western blot analysis and SSAT enzymatic activities by the conversion of [1-14C]acetyl-CoA into [1-14C]acetylspermidine. Polyamine [i.e. putrescine (PUT), spermine (SPM) and spermidine (SPD)] levels were measured with high-performance liquid chromatography. DENSPM enhanced the efficacy of radiation treatment in HCT116, HCT116-Clone2 (a radiation-resistant clone) and HCT116-Clone10 (a clone with similar X-radiation response as the parental HCT116 cells) but not in HCT116-CloneK (an X-radiation-sensitive but relatively drug-resistant clone). Treatment with DENSPM without X radiation caused the most significant increase in SSAT activity (approximately 22-fold) and an almost complete depletion of SPD levels in HCT116-CloneK. Our results suggest that (a) the lack of sensitization of X-radiation treatment by DENSPM in HCT116-CloneK was likely due to the prior depletion of SPD levels by DENSPM alone, (b) natural polyamine contents and/or inducibility of SSAT may be important factors influencing cellular response to combined X-radiation and DENSPM treatments, and (c) more importantly, there may be a potentially novel role for combining polyamine analogs such as DENSPM with X rays.
Qutob
Sami S
SS
Centre for Cancer Therapeutics, Ottawa Regional Cancer Centre, Ottawa, Ontario, K1H 1C4, Canada.
Proulx
Denise
D
Mesak
Felix M
FM
Ng
Cheng E
CE
D000970:Antineoplastic Agents / Q000008:administration & dosage; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects* / Q000528:radiation effects*; D003001:Cloning, Molecular / Q000379:methods; D015179:Colorectal Neoplasms / Q000145:classification / Q000188:drug therapy* / Q000235:genetics / Q000532:radiotherapy*; D003131:Combined Modality Therapy; D004305:Dose-Response Relationship, Drug; D004307:Dose-Response Relationship, Radiation; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects; D006801:Humans; D011836:Radiation Tolerance / Q000187:drug effects; D013096:Spermine / Q000008:administration & dosage* / Q000031:analogs & derivatives*; D016896:Treatment Outcome; D014964:X-Ray Therapy / Q000379:methods
D000970:Antineoplastic Agents; C059685:N(1),N(11)-diethylnorspermine; D013096:Spermine