Radiation therapy of small cell lung cancer with 177Lu-DOTA-Tyr3-octreotate in an animal model.
Small cell lung cancer (SCLC) is a tumor of neuroendocrine (NE) origin with very low survival rate. Somatostatin receptor scintigraphy using 111In-DTPA-octreotide (DTPA is diethylenetriaminepentaacetic acid) is a well-established method for the visualization of somatostatin receptor-expressing NE tumors. Recently, new combinations of radionuclides and somatostatin analogs have been investigated for therapeutic purposes. In this study, the somatostatin analog DOTA-Tyr3-octreotate (DOTA is 1,4,7,10-tetraazacyclododecane-N,N',N",N"'-tetraacetic acid), labeled with the medium-energy electron emitter 177Lu (maximal electron energy = 498 keV, half-life = 6.6 d), was used for radiation therapy of human SCLC in an animal model.


METHODS
Nude mice, bearing tumors from the human SCLC cell line NCI-H69, were injected intravenously with 177Lu-DOTA-Tyr3-octreotate. Groups of animals (n = 5 or 6) were injected with 45-, 60-, and 120-MBq fractions and two 45-MBq fractions 48 h apart. Furthermore, 1 control group was treated with unlabeled DOTA-Tyr3-octreotate and another control group was not treated.


RESULTS
In both control groups, the tumor volumes were increased 2-fold in approximately 5 d. Treatment with 177Lu-DOTA-Tyr3-octreotate resulted in marked tumor regression with statistically significant tumor volume reduction after 1 wk (P < 0.001). The tumor growth delay time was dependent on the amount of injected activity for the groups with single injections, 26 d for 60 MBq and 40 d for 120 MBq. The best therapeutic effect was obtained in mice injected with 2 fractions of 45 MBq. The relative tumor volume after 1 mo was 0.004 +/- 0.004.


CONCLUSIONS
Radiation therapy with 177Lu-DOTA-Tyr3-octreotate on SCLC-bearing mice was successful. Since the experiments were performed on a human SCLC cell line xenografted to nude mice, the results may be clinically relevant and treatment with 177Lu-DOTA-Tyr3-octreotate could be a treatment alternative in this tumor disease that normally has a dismal prognosis.
Schmitt
Anneli
A
Department of Radiation Physics, Lundberg Laboratory for Cancer Research, Sahlgrenska University Hospital, Göteborg University, Göteborg, Sweden. anneli.schmitt@radfys.gu.se
Bernhardt
Peter
P
Nilsson
Ola
O
Ahlman
Håkan
H
Kölby
Lars
L
Maecke
Helmut R
HR
Forssell-Aronsson
Eva
E
D000818:Animals; D018288:Carcinoma, Small Cell / Q000378:metabolism* / Q000532:radiotherapy*; D004195:Disease Models, Animal; D007275:Injections, Intravenous; D008175:Lung Neoplasms / Q000378:metabolism / Q000532:radiotherapy; D008297:Male; D008657:Metabolic Clearance Rate; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015282:Octreotide / Q000031:analogs & derivatives; D009928:Organ Specificity; D009942:Organometallic Compounds / Q000008:administration & dosage / Q000493:pharmacokinetics* / Q000627:therapeutic use*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D014018:Tissue Distribution; D016896:Treatment Outcome
D009942:Organometallic Compounds; D019275:Radiopharmaceuticals; C447941:lutetium Lu 177 dotatate; D015282:Octreotide