Chemopotentiation in vivo: no loss of sensitization with fractionation.

Abstract

The response of KHT sarcomas to one, two, five or ten daily fractions of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), with and without misonidazole (MISO), was evaluated using delay of tumour regrowth as the measure of response. When CCNU was given as 2 dose fractions separated by 24 h rather than as a single treatment, no extra dose was necessary to achieve a particular level of damage, suggesting a lack of damage repair. With increasing fraction number, however, an increasing total dose of drug was required to achieve a given effect, presumably to compensate for proliferation. Increasing drug doses also were readily tolerated (almost twice the LD50/7 for a single dose of CCNU resulted in no deaths when given in a 10 fraction treatment) indicating a large sparing of normal tissue toxicity when CCNU treatments were fractionated. The addition of MISO enhanced the tumour response to CCNU in all treatment schemes. When single doses of CCNU were combined with 0.5 mg g-1 MISO, an enhancement ratio (ER) of approximately 1.5 was observed. This ER was maintained for all fractionated treatment schedules including the 10 daily fraction protocol. In addition, no loss of sensitization with increasing fractionation was observed when a lower dose of 0.2 mg g-1 MISO was combined with each of 5 or 10 daily fractions of CCNU. Similar experiments were performed to test the combination of cyclophosphamide (Cy) and MISO (0.5 mg g-1) in the RIF-1 tumour; again chemopotentiation was maintained with increasing fractionation. These results of combined MISO and fractionated chemotherapy are in contrast to the rapid loss of sensitization observed when MISO is used as a radiation sensitizer and combined with small doses of X-rays, thus providing in vivo evidence of the mechanistic difference between the effects of MISO used as a radiation sensitizer or chemopotentiator. Peripheral white blood cell counts performed on mice receiving 5 daily fractions of CCNU +/- MISO displayed no significant enhancement of normal tissue toxicity by MISO. Thus combining MISO with repeated low dose treatments of a chemotherapeutic agent results in a therapeutic gain.