title: Induction of cancer metastasis by cyclophosphamide pretreatment of host mice: an opposite effect of chemotherapy.
abstract: Although side effects of cancer chemotherapy are well known, "opposite effects" of chemotherapy that enhance the malignancy of the treated cancer are not well understood. In this report, we describe the induction of intravascular proliferation, extravasation, and colony formation by cancer cells, critical steps of metastasis, by pretreatment of host mice with the commonly used chemotherapy drug cyclophosphamide. In contrast, in the unpretreated mice, most cancer cells remained quiescent in vessels without extravasation. HT1080 human fibrosarcoma cells, labeled in the nucleus with green fluorescent protein and red fluorescent protein in the cytoplasm for imaging, were injected into the epigastric cranialis vein of nude mice. Twenty-four hours before cancer cell injection, cyclophosphamide was given i.p. Double-labeled cancer cells were imaged at the cellular level in live mice with the Olympus OV100 Small Animal Imaging System with variable magnification. Cyclophosphamide seems to interfere with a host process that inhibits intravascular proliferation, extravasation, and extravascular colony formation. Cyclophosphamide does not directly affect the cancer cells because cyclophosphamide has been cleared by the time the cancer cells were injected. This report shows an important unexpected "opposite effect" of chemotherapy that enhances critical steps in malignancy rather than inhibiting them, suggesting that certain current approaches to cancer chemotherapy should be modified.
authors.affiliation: AntiCancer, Inc., San Diego, CA 92111, USA.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Yamauchi
authors.forename: Meng
authors.initials: M
authors.lastname: Yang
authors.forename: Katsuhiro
authors.initials: K
authors.lastname: Hayashi
authors.forename: Ping
authors.initials: P
authors.lastname: Jiang
authors.forename: Norio
authors.initials: N
authors.lastname: Yamamoto
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tsuchiya
authors.forename: Katsuro
authors.initials: K
authors.lastname: Tomita
authors.forename: Abdool R
authors.initials: AR
authors.lastname: Moossa
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
mesh_terms: D000818:Animals; D018906:Antineoplastic Agents, Alkylating / Q000009:adverse effects / Q000627:therapeutic use; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D003520:Cyclophosphamide / Q000009:adverse effects* / Q000627:therapeutic use*; D005354:Fibrosarcoma / Q000139:chemically induced* / Q000556:secondary*; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis; D009368:Neoplasm Transplantation; D011292:Premedication / Q000009:adverse effects*; D047368:Tumor Burden / Q000187:drug effects; D014407:Tumor Cells, Cultured; D019043:Vascular Neoplasms / Q000139:chemically induced* / Q000556:secondary*
chemical_list: D018906:Antineoplastic Agents, Alkylating; D003520:Cyclophosphamide