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: Kensuke Yamauchi, Meng Yang, Katsuhiro Hayashi, Ping Jiang, Norio Yamamoto, Hiroyuki Tsuchiya, Katsuro Tomita, Abdool R Moossa, Michael Bouvet, Robert M Hoffman
• Journal: Cancer research (Cancer Res) Vol. 68 Issue 2 Pg. 516-20 (Jan 15 2008) ISSN: 1538-7445 [Electronic] United States
• PMID: 18199547 (Publication Type: Evaluation Study, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents, Alkylating
• Cyclophosphamide

Topics

• Animals
• Antineoplastic Agents, Alkylating (adverse effects, therapeutic use)
• Cell Adhesion (drug effects)
• Cell Proliferation (drug effects)
• Cyclophosphamide (adverse effects, therapeutic use)
• Fibrosarcoma (chemically induced, secondary)
• Humans
• Mice
• Mice, Nude
• Neoplasm Metastasis
• Neoplasm Transplantation
• Premedication (adverse effects)
• Tumor Burden (drug effects)
• Tumor Cells, Cultured
• Vascular Neoplasms (chemically induced, secondary)