Antiproliferative effects of corticosteroids in C3H/HeJ Mammary tumors and implications for sequential combination...

Corticosteroid-induced inhibition of cell proliferation and tumor growth was studied in first-generation transplants (FGMT) of spontaneous C3H/HeJ mammary tumors (SMT). Competitive binding studies using the dextran-coated charcoal method demonstrated that both SMT and FGMT exhibit high-affinity, low-capacity cytoplasmic binding sites for corticosteroids. Free cytoplasmic binding sites, determined by Scatchard analysis of dexamethasone (DEX) binding data, were more abundant in SMT (323 +/- 45 fmol/mg) than in FGMT (199 +/- 35 fmol/mg). Apparent dissociation constants, 3.83 +/- 1.14 and 5.06 +/- 1.53 nM for SMT and FGMT, respectively, were consistent with those found in other corticosteroid-sensitive tissues. In vivo treatment of FGMT with DEX or methylprednisolone resulted in dose-dependent inhibition of cell proliferation and tumor growth. The recovery kinetics after three doses of either methylprednisolone or DEX (10 mg/kg every 12 hr) suggested reversible G1 progression delay. Changes in the [3H]thymidine labeling index after steroid treatment indicated maximal S-phase cellularity 18 to 24 hr after methylprednisolone and 42 to 48 hr after DEX. On the basis of regrowth delay measurements, the effectiveness of sequential therapy with corticosteroids and either 5-fluorouracil or especially vincristine was seen to be time sequence dependent. The most effective intervals were those in which vincristine and/or 5-fluorouracil was given to coincide with maximal S-phase cellularity after steroid treatments.