Although side effects of cancer chemotherapy are well known, "opposite effects" of chemotherapy which enhance the
malignancy of the treated cancer are not well understood. We have observed a number of steps of malignancy that are
enhanced by chemotherapy pre-treatment of mice before transplantation of human tumor cells. The induction of
intravascular proliferation, extravasation, and colony formation by cancer cells, critical steps of metastasis was
enhanced by pretreatment of host mice with the commonly-used chemotherapy drug cyclophosphamide.
Cyclophosphamide appears to interfere with a host process that inhibits intravascular proliferation, extravasation, and
extravascular colony formation by at least some tumor cells. Cyclophosphamide does not directly affect the cancer cells
since cyclophosphamide has been cleared by the time the cancer cells were injected. Without cyclophosphamide
pretreatment, human colon cancer cells died quickly after injection in the portal vein of nude mice. Extensive
clasmocytosis (destruction of the cytoplasm) of the cancer cells occurred within 6 hours. The number of apoptotic cells
rapidly increased within the portal vein within 12 hours of injection. However, when the host mice were pretreated with
cyclophosphamide, the cancer cells survived and formed colonies in the liver after portal vein injection. These results
suggest that a cyclophosphamide-sensitive host cellular system attacked the cancer cells. This review describes an
important unexpected "opposite effects" of chemotherapy that enhances critical steps in malignancy rather than
inhibiting them, suggesting that certain current approaches to cancer chemotherapy should be modified.