Inhibition of mouse mammary adenocarcinoma (EMT6) growth and metastases in mice by a modified form of C-reactive protein.
Mice were injected in the hind limb with a mouse mammary adenocarcinoma cell line, EMT6, and tumor growth at the primary site as well as the incidence of lung metastases were measured. Groups of animals were treated with the acute-phase reactant C-reactive protein, (native-CRP), or a conformationally modified form of CRP (mCRP) made by dissociating CRP subunits under chelating, denaturing conditions. Each form of CRP was injected (intravenously) through the tail vein, encapsulated in large unilamellar lipid vesicles made by an extrusion technique (LUVETs). mCRP was also injected without the LUVET carrier. Mice not treated, or treated with LUVETs alone, exhibited both progressive tumor growth at the primary site and a high incidence of metastatic lung tumors quantified at necropsy. Treatment with native-CRP encapsulated in LUVETs had little or no effect on either tumor growth or metastases. Treatment with mCRP, however, alone or encapsulated in LUVETs, effectively slowed or stopped the progression of tumor growth, and in some mice, showed a decrease in tumor size. After cessation of mCRP injections, tumor growth resumed at a rate comparable to that measured in untreated animals. Fifty to 85% of mice treated with mCRP or mCRP in LUVETs developed necrotic lesions at the primary tumor site within 24-48 h following the initial injection of protein. Furthermore, at necropsy, only 6% of mice treated with mCRP in LUVETs and 40% of mice treated with mCRP alone showed evidence of lung metastases compared to 67-80% of animals in no-treatment, native-CRP in LUVETs and in LUVET control group animals. These results show that the prototypic acute-phase reactant, CRP, has therapeutic anticancer and antimetastatic activity only when the native pentameric subunit structure is dissociated to form the mCRP conformer.
Department of Cell and Molecular Biology, Northwestern University Medical School, Chicago, Ill., USA.
J J
JJ
Kresl
L A
LA
Potempa
B
B
Anderson
J A
JA
Radosevich
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002097:C-Reactive Protein / Q000008:administration & dosage* / Q000009:adverse effects / Q000276:immunology / Q000494:pharmacology*; D004339:Drug Compounding; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000517:prevention & control / Q000556:secondary; D008247:Lysosomes / Q000378:metabolism; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009362:Neoplasm Metastasis / Q000517:prevention & control; D009368:Neoplasm Transplantation; D011487:Protein Conformation; D011489:Protein Denaturation; D014407:Tumor Cells, Cultured
D002097:C-Reactive Protein