Inhibition of tumor progression and paraneoplastic syndrome development in a murine lung adenocarcinoma by medroxyprogesterone acetate and indomethacin.
Mice bearing LP07 lung adenocarcinoma present some characteristics similar to those shown in patients with several malignant diseases. LP07 tumor bearers develop paraneoplastic syndromes such as cachexia, leukocytosis, and hypercalcemia, partly due to a systemic inflammatory response. We analyzed some of the mechanisms involved in the effectiveness of the association of the appetite-stimulant medroxiprogesterone acetate (MPA) and the nonselective cyclooxigenase (COX) inhibitor indomethacin (INDO) in LP07 tumor bearing mice. INDO and INDO plus MPA treatments significantly inhibited tumor growth, which was not inhibited by MPA. The number of lung metastatic nodules was decreased with all treatments, being most effective INDO alone and INDO plus MPA. A significant decrease of plasmatic levels of the matrix metalloproteinases MMP-9 and MMP-2 correlated with these results. Paraneoplastic syndromes, leukocytosis, and cachexia were abolished by all treatments. We determined effects of the treatments on circulating cytokines shown to regulate cachexia and inflammation. Both treatments alone, and INDO plus MPA, reduced circulating IL-6 throughout tumor evolution. A pronounced increase in serum IL-1ss levels was detected in untreated tumor bearers. These levels decreased and were closer to normal serum values when LP07 mice were treated with INDO plus MPA. The combination of a nonsteroidal antiinflammatory drug as INDO and MPA showed to be effective in inhibiting tumor and metastatic growth and diminishing paraneoplastic symptoms and SIR. A variety of specific molecules are implicated as playing a role in cancer-induced cachexia and hematological alterations.
Animal Care and Experimental Cancer Department, Angel H. Roffo Institute of Oncology, University of Buenos Aires, Buenos Aires, Argentina. bioterioroffo@fmed.uba.ar
Miriam Judith
MJ
Diament
Guillermo Daniel
GD
Peluffo
Isabel
I
Stillitani
Leandro Carlos
LC
Cerchietti
Alfredo
A
Navigante
Stella Maris
SM
Ranuncolo
Slobodanka Mariana
SM
Klein
D000230:Adenocarcinoma / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage; D018931:Antineoplastic Agents, Hormonal / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols; D019167:Appetite Stimulants / Q000008:administration & dosage; D002100:Cachexia / Q000209:etiology / Q000517:prevention & control; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006934:Hypercalcemia / Q000209:etiology / Q000517:prevention & control; D007213:Indomethacin / Q000008:administration & dosage; D007375:Interleukin-1 / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D008175:Lung Neoplasms / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000097:blood / Q000187:drug effects; D020780:Matrix Metalloproteinase 9 / Q000097:blood / Q000187:drug effects; D017258:Medroxyprogesterone Acetate / Q000008:administration & dosage; D051379:Mice; D008807:Mice, Inbred BALB C; D010257:Paraneoplastic Syndromes / Q000517:prevention & control*
D000894:Anti-Inflammatory Agents, Non-Steroidal; D018931:Antineoplastic Agents, Hormonal; D019167:Appetite Stimulants; D007375:Interleukin-1; D015850:Interleukin-6; D017258:Medroxyprogesterone Acetate; D020778:Matrix Metalloproteinase 2; D020780:Matrix Metalloproteinase 9; D007213:Indomethacin