title: Liposome-encapsulated hemoglobin enhances chemotherapy to suppress metastasis in mice.
abstract: Liposome-encapsulated hemoglobin with high O2 -affinity (P50 O2  = 10 mm Hg, h-LEH) was reported to enhance tumor radiosensitivity. We hypothesize that targeted O2 delivery to tumor hypoxia by h-LEH may also enhance chemotherapy to suppress tumor growth and metastasis in mice. Doxorubicin (DXR; 0.5 or 2 mg/kg i.p.) or S-1 (4 or 8 mg/kg orally) alone or in combination with h-LEH (5 mL/kg i.v.) was administered for 2 weeks to C57BL/6N mice inoculated with Lewis Lung Carcinoma (LLC) in the leg. After the 2-week therapy in six treatment groups, mice were sacrificed for quantitative assessment of tumor growth and lung metastasis. The tumor was then evaluated for its expression of hypoxia-inducible factor-1α (HIF-1α) and matrix metallopoteinase-2 (MMP-2) activity. Combined use of h-LEH and chemotherapeutic agents (DXR or S-1) showed no additional enhancement on suppression of the tumor growth over the chemotherapeutic agent alone. However, the combination use of h-LEH significantly suppressed the number and total area of metastatic colonies in the lung compared with each chemotherapeutic agent alone. Although HIF-1α expression and MMP-2 activity in the original tumor was significantly suppressed in the groups of mice treated with either DXR or S-1 alone, the addition of h-LEH to either agent showed further enhancement of oxygen-mediated degradation of HIF-1α and suppression of MMP-2 activity. Although the addition of h-LEH to DXR or S-1 had little effect on original LLC tumor growth, it significantly enhanced suppression of lung metastasis in mice.
authors: Department of Clinical Pharmacology, Tokai University School of Medicine, Isehara, Japan.
authors: Chieko
authors: C
authors: Murayama
authors: Akira T
authors: AT
authors: Kawaguchi
authors: Akemi
authors: A
authors: Kamijo
authors: Katsuko
authors: K
authors: Naito
authors: Kayoko
authors: K
authors: Iwao
authors: Hideo
authors: H
authors: Tsukamoto
authors: Kayo
authors: K
authors: Yasuda
authors: Yasukazu
authors: Y
authors: Nagato
mesh_terms: D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000627:therapeutic use; D001802:Blood Substitutes / Q000494:pharmacology / Q000627:therapeutic use*; D004317:Doxorubicin / Q000627:therapeutic use; D016503:Drug Delivery Systems; D005260:Female; D006454:Hemoglobins / Q000494:pharmacology / Q000627:therapeutic use*; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D008081:Liposomes / Q000494:pharmacology / Q000627:therapeutic use*; D008168:Lung / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D051379:Mice; D009362:Neoplasm Metastasis / Q000188:drug therapy* / Q000473:pathology; D009368:Neoplasm Transplantation
chemical_list: D000903:Antibiotics, Antineoplastic; D001802:Blood Substitutes; D006454:Hemoglobins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D008081:Liposomes; D004317:Doxorubicin; D020778:Matrix Metalloproteinase 2
keywords: Cancer chemotherapy; Liposome-encapsulated hemoglobin; Metastasis; Tumor growth