Potential of the aminosterol, squalamine in combination therapy in the rat 13,762 mammary carcinoma and the murine Lewis lung carcinoma.
Squalamine, a naturally-occurring aminosterol, has demonstrated antiangiogenic activity in several experimental models. Extended treatment with other antiangiogenic agents has been shown to increase tumor oxygenation. Tumor oxygenation was measured using an Eppendorf pO2 histograph polarographic pO2 electrode system in the rat 13,762 mammary carcinoma after treatment of the tumor-bearing animals with squalamine (40 mglkg) on days 4 through 18 post tumor implantation. Under air breathing conditions, the hypoxic fraction (percent of pO2 readings < 5 mmHg) was 53% in controls and was decreased to 38% in the squalamine treated animals. While squalamine administration alone produced only a modest effect on the growth of the 13,762 tumor, there were increases in tumor growth delay of 1.9- to 2.5-fold when squalamine was administered along with cyclophosphamide, cisplatin and paclitaxel compared with the tumor growth delays observed with the chemotherapeutic agents alone. To determine the efficacy of squalamine alone and along with cytotoxic therapies against a model of primary and systemic disease, squalamine was administered to animals bearing the Lewis lung carcinoma by daily subcutaneous injection or by continuous infusion on days 4 through 18 post tumor implantation. Squalamine as a single agent had only a modest effect on the growth of the primary Lewis lung tumor but increased the tumor growth delays produced by cyclophosphamide, cisplatin, paclitaxel and 5-fluorouracil by 2.4- to 3.8-fold compared with the anticancer drugs alone. Squalamine administration alone substantially decreased the number of lung metastases found in animals bearing the Lewis lung carcinoma and further decreased the number of lung metastases when administered along with the chemotherapeutic agents.
Dana-Farber Cancer Institute and Joint Center for Radiation Therapy, Boston, MA 02115, USA. TEICHERvBEVERLYvA@LILLY.COM
B A
BA
Teicher
J I
JI
Williams
H
H
Takeuchi
G
G
Ara
R S
RS
Herbst
D
D
Buxton
D015127:9,10-Dimethyl-1,2-benzanthracene; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use*; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control* / Q000532:radiotherapy; D002455:Cell Division / Q000187:drug effects; D002777:Cholestanols / Q000627:therapeutic use; D002945:Cisplatin / Q000627:therapeutic use; D003131:Combined Modality Therapy; D003520:Cyclophosphamide / Q000627:therapeutic use; D004317:Doxorubicin / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005260:Female; D005472:Fluorouracil / Q000627:therapeutic use; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology / Q000517:prevention & control* / Q000532:radiotherapy; D051379:Mice; D010100:Oxygen / Q000032:analysis; D010101:Oxygen Consumption / Q000187:drug effects; D017239:Paclitaxel / Q000627:therapeutic use; D010313:Partial Pressure; D051381:Rats; D011916:Rats, Inbred F344
D016588:Anticarcinogenic Agents; D000970:Antineoplastic Agents; D002777:Cholestanols; D015127:9,10-Dimethyl-1,2-benzanthracene; D004317:Doxorubicin; D003520:Cyclophosphamide; C079655:squalamine; D017239:Paclitaxel; D002945:Cisplatin; D010100:Oxygen; D005472:Fluorouracil