Experimental Study Of Bladder Cancer Internal Radiation Therapy By 5-[～(125)I]iodo-2'-deoxyuridine

【Objective】To study the radioactivity distribution and safety of5-[¹²⁵â… ]iodo-2'-deoxyuridine(¹²⁵IUdR) after intravesical instillation of ¹²⁵IUdR in nude micebearing bladder cancer. To investigate the efficacy and feasibility of bladder cancer byintravesical instillation of ¹²⁵IUdR.【Methods】(1)The model of orthotopic transplantation bladder cancer was copied onBALB/nu/nu mice.The nude mice bearing bladder Cancer were randomly assigned to twogroups:experimental group and control group.Two groups of mice were administrateddifferent dose of ¹²⁵IUdR and Na¹²⁵â… respectively by intravesical instillation.Thedistribution of ¹²⁵IUdg was estimated by means of single photon emission tomographyscintigrams(SPECT) and the radioactivity of various organs was determined bygamma-counter after intravesical instillation of ¹²⁵IUdR.The pharmic safety was evaluatedby using hemogram and flow biochemistry indexes:alanine aminotransferase(ALT),aspartate aminotransferase(AST),blood urea nitrogen (BUN),creatinine(Cr).(2)The modelof orthotopic bladder cancer was copied on BALB/nu/nu mice.The nude mice beatingbladder cancer were randomly assigned to four groups:negative control group,positivecontrol group,simple experimental group and combined experimental group.The nudemice bearing bladder cancer of every group were given normal saline,mitomycin(MMC), ¹²⁵IUdR and ¹²⁵IUdR combined with methotrexate(MTX) every timean hour ahead of intravesical instillation by intraperitoneal injection separately once everyfive days during twenty days.Every group was taken three mice for survival analysis insixty days.The therapeutic effect of every group was comparced through flowcytometry(FCM), expression of p21 gene messenger RNA by real time polymerase chain reaction(PCR),pathologic,terminal deoxynucleotidyl transferase mediated dUTP nickendlabeling(YUNEL), caspase-3 and survival analysis.【Results】(1)After intravesical instillation the distribution of ¹²⁵IUdR was mainly inbladder cancer of the mice bearing bladder cancer.The relative value of bladder and musclewas significantly larger in experimental group than in control group.The changes ofhemogram and flow biochemistry indexes were not observed after intravesicaladministration of ¹²⁵IUdR in the mice bladder bearing bladder cancer.(2)The bladderweight of mice bearing bladder tumor were significantly smaller in experimental group andpositive control group than in negative control group,and the bladder weight of mice weresmaller in combined experimental group than in simple experimental group and positivecontrol group.(3)The detection of flow cytometry demonstrate that S-phase percentage oftumor cell was strikingly lower in experimental group than in negative control group,on theother hand apoptotic index of tumor cell was obviously higher than the latter.(4)Themessenger RNA level of p21 gene was strikingly higher in experimental group than innegative control group.(5)The analysis of TUNEL and caspase-3 display that apoptosiscells were obviously higher in experimental group than in negative control group.(6)Thesurvival time of mice bearing bladder cancer were much longer in experimental group thanin negative control group.【Conclusions】(1)¹²⁵IUdR used for intravesical instillation could improve theconcentration of ¹²⁵IUdR in local tissues,prolong the acting time in target organ(bladder)and reduce the side-effect to surrounding normal tissues.¹²⁵IUdR is a promising agent intreating of bladder cancer.(2)The induction of orthotopic transplantation bladder cancerwas 100%,most tumors were superficial in early stage,which well simulated biologicalbehavior of human bladder cancer.(3)¹²⁵IUdR can selectively kill S-phase tumorcells,suppressed tumor cell proliferation,obstructed the DNA synthesis of tumor cell,increased theexpression of p21 gene in tumor cells,and extended the survival of tumor-bearingmice.(4)Therapeutic effect of ¹²⁵IUdR is similatr to the therapeutic effect ofchemotherapeutics mitomycin which is commonly used in clinic,but the side effect of ¹²⁵IUdR is obviously less than that of mitomycin.(5)The combination of ¹²⁵IUdR andMTX showed synergistic effect and enhanced therapeutic effect.