ABSTRACT
Chronic deprivation of nutrients is rare in normal tissues, however large areas of tumor are nutrient-starved and hypoxic due to a disorganized vascular system. Some cancers show an inherent ability to tolerate severe growth conditions. Therefore, we screened chemical compounds to identify cytotoxic agents that function preferentially in nutrient-deprived conditions. We found that AG1024, a specific inhibitor of insulin-like growth factor-1 receptor tyrosine kinase (IGF-1R), showed preferential cytotoxicity to human pancreatic cancer cells in nutrient-deprived conditions relative to cells in nutrient-sufficient conditions. The cytotoxicity of I-OMe-AG538 (another specific inhibitor of IGF-1R kinase) was also enhanced in nutrient-deprived cells. In addition, AG1024 and I-OMe-AG538 potently inhibited IGF-1R activation to nutrient-deprived cells. In contrast, conventional chemotherapeutic drugs, as well as inhibitors of PDGFR and EGFR kinases, elicited weak cytotoxicity. These data indicate that nutrient-deprived human pancreatic cancer cells have increased sensitivity to inhibition of IGF-1R activation. IGF-1R inhibitors offer a promising strategy for anticancer therapeutic approaches that are oriented toward tumor microenvironment.
Subject(s)
Antineoplastic Agents/pharmacology , Pancreatic Neoplasms/enzymology , Protein Kinase Inhibitors/pharmacology , Receptor, IGF Type 1/antagonists & inhibitors , Tyrphostins/pharmacology , Antineoplastic Agents/chemistry , Antineoplastic Agents/isolation & purification , Cell Survival/drug effects , Drug Screening Assays, Antitumor , Humans , Protein Kinase Inhibitors/chemistry , Protein Kinase Inhibitors/isolation & purification , Tyrphostins/chemistryABSTRACT
Kigamicin D did not show any immunosuppressive activity in mixed lymphocyte culture reaction and mitogen induced lymphocyte blastogenesis in vitro and graft versus host reaction in vivo. Natural killer cell activity in spleen cells was not affected by oral administration of kigamicin D. Instead, delayed-type hypersensitivity response to sheep red blood cells was stimulated at a broad dosage level. It is concluded that kigamicin D increases cellular immunity to specific antigen.
Subject(s)
Doxorubicin/analogs & derivatives , Immunity, Cellular/drug effects , Oxazoles/pharmacology , Animals , Cells, Cultured , Doxorubicin/pharmacology , Graft vs Host Reaction/drug effects , Hypersensitivity, Delayed , Killer Cells, Natural/drug effects , Lymphocyte Activation/drug effects , Lymphocyte Culture Test, Mixed , Mice , Mice, Inbred C3H , Models, Animal , Spleen/immunologyABSTRACT
Kigamicin D is a novel anticancer agent that was identified using a new screening strategy that targets the tolerance of cancer cells to nutrient starvation [1, 2]. Oral administration of kigamicin D was previously described to show a strong antitumor effect in human tumor xenograft models of pancreatic tumors [2]. In this paper we describe that kigamicin D shows the same selective cytotoxicity against normal human cells such as lung fibroblast and prostate stromal cells under nutrient starved condition as against cancer cells. Kigamicin D inhibited tumor cell-induced angiogenesis in a dorsal air sac assay. On the basis of these results we tested other human tumor xenograft models and transplantable syngeneic tumor models in order to determine the spectrum of activity of kigamicin D against various cancers. Kigamicin D showed a weak antitumor effect against LX-1 and DMS-273 lung cancers, but had no effect on DLD-1 colon cancers. When tested against syngeneic tumors, kigamicin D showed a weak antitumor effect against colon26, but showed augmentation of tumor growth on IMC carcinoma at a broad dosage level. Kigamicin D does not show good antitumor activity against human xenograft tumors except pancreatic tumors and murine syngeneic tumors. We found that kigamicin D has excellent antitumor effect specific to pancreatic cancers. Surprisingly, high dosage of kigamicin D increased tumor growth of IMC carcinoma by than 200%. The phenomenon suggests that kigamicin D may cause some immunological response to the tumor.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Doxorubicin/analogs & derivatives , Neoplasms/drug therapy , Oxazoles/therapeutic use , Animals , Antibiotics, Antineoplastic/pharmacology , Cell Line, Tumor , Colonic Neoplasms/drug therapy , Disease Models, Animal , Doxorubicin/pharmacology , Doxorubicin/therapeutic use , Female , Humans , Lung Neoplasms/drug therapy , Mice , Mice, Inbred BALB C , Neoplasm Transplantation , Neoplasms/pathology , Neovascularization, Pathologic/prevention & control , Oxazoles/pharmacology , Pancreatic Neoplasms/drug therapy , Xenograft Model Antitumor AssaysABSTRACT
In the course of screening for inhibitors of osteoclastogenesis, a new substance designated as ICM0201 was isolated from a fermentation broth of Cunninghamella sp. F-1490. ICM0201 inhibited the formation of osteoclasts in mouse bone marrow cells with an IC50 value of 0.78 microg/ml and showed weak cytotoxicity against bone marrow cells.
