[Tumor growth inhibition of paclitaxel-octreotide conjugates on human non small cell lung cancer: experiment with mice].
OBJECTIVE
To evaluate the antitumor effects of the conjugates synthesized by coupling cytotoxic paclitaxel (PTX) to somatostatin analog octreotide (OCT) on human non small cell lung cancer (NSCLC).


METHODS
Two cytotoxic somatostatin analog, PTX-OCT and 2PTX-OCT, were developed in which PTX was linked to octreotide. Forty-five BALB/c nu/nu nude mice were injected with human NSCLC cells of the line A549 into the right armpit. The nude mice that were xenografted were randomly divided into 8 groups. (1) control group (n = 6), (2) PTX-OCT group (n = 5), injected intravenously with PTC-OCT 150 nmol/kg on days 1, 7, and 21, (3) 2PTX-OCT group (n = 6), injected intravenously with PTC-OCT 150 nmol/kg, (4) OP group (n = 6), injected with mixture of PTX and OCT 150 nmol/kg, (5) OCT group (n = 5) injected with OCT 150 nmol/kg (6) PTX group (n = 6), injected with PTX 150 nmol/kg, (7) 2PTX group, injected with PTX 300 nmol/kg, and (8) 2(PTX-OCT) injected with PTX-OCT 300 nmol/kg, The tumor volume and body weight (BW) were observed regularly. The tumor volume doubling time was calculated. White blood cells were counted by collecting peripheral blood sample. By the end of experiment the mice were killed with the tumors taken out. The expression of mRNA of subtypes1-5 of human somatostatin receptor (SSTR1-SSTR5) were investigated using RT-PCR. Histological apoptosis was detected by DNA ladder. Immunohistochemistry was used to examine the SSTR2 and SSTR5 expression and tumor microvessel density (MVD).


RESULTS
The tumor volumes of 2PTX-OCT and 2(2PTX-OCT) groups were significantly smaller than those of other groups (all P < 0.01). The tumor doubling times of the 2PTX-OCT and 2 (2PTX-OCT) groups were significantly longer than those of the other groups too (all P < 0.01). The MVD levels of the 2PTX-OCT and 2 (2PTX-OCT) groups were significant lower than those of the other groups (all P < 0.01). The toxicity of the PTX group was more obvious. The WBC count levels of the PTX and 2PTX groups were significantly lower than those of the other groups (all P < 0.05). mRNA expression could be found for SSTR1, 2, 4, and 5 in the A549 xenografts. Immunohistochemistry showed that SSTR2 was mainly found in the tumor cell membrane, and SSTR5 was found in the tumor cell membrane and cytoplasm. More histological apoptosis bands were shown by DNA ladder method in the 2PTX-OCT and 2 (PTX-OCT) groups.


CONCLUSIONS
The targeting conjugate 2PTX-OCT inhibits the proliferation of tumor cells, reduces microvessel, and decreases the toxicity in comparison with the cytotoxic radical PTX.
Shen
Hong-Chang
HC
Department of Oncology, Qilu Hospital, Shandong University, Jinan 250012, China.
Wang
Xiu-Wen
XW
Liu
Yan-Guo
YG
D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis; D002289:Carcinoma, Non-Small-Cell Lung / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D006801:Humans; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy* / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D055806:Microvessels; D015282:Octreotide / Q000627:therapeutic use*; D017239:Paclitaxel / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000235:genetics; D017481:Receptors, Somatostatin / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
D000970:Antineoplastic Agents; D012333:RNA, Messenger; D017481:Receptors, Somatostatin; C492049:Sstr2 protein, mouse; C094573:somatostatin receptor 5; D017239:Paclitaxel; D015282:Octreotide