Recruitment of noncycling tumor cells into proliferation by isoproterenol

The resistance of tumors to conventional anticancer therapy is partially determined by the fraction of noncycling cells they contain. In several normal tissues, isoproterenol can stimulate cell proliferation. The effect of isoproterenol on the EMT6/St tumor grown both intradermally in BALB/c mice and in vitro as multicell spheroids was investigated. The incorporation of [3H]thymidine (5 microCi/g, 6.7 Ci/mmol) into DNA was determined as a function of time after i.p. injection of isoproterenol (0.15 mg/g). Tissue section autoradiographs of the EMT6 tumors were prepared, and labeling indices were determined. EMT6 spheroids were exposed to isoproterenol and labeled with [3H]thymidine in a manner designed to simulate drug exposure in vivo. In EMT6 tumors, the labeling index rose from a control level of 30% to a peak of 53% at 25 hr; it then declined gradually for the next 30 hr. This may be interpreted as evidence that cells were recruited into proliferation. In contrast, isoproterenol had minimal effects on EMT6 spheroids, implying that recruitment caused by this drug was not a direct effect on individual cells.