A preclinical model for sequential high-dose chemotherapy.
Dose-intensive chemotherapy regimens have entered clinical trial based on the notion that log-linear tumor-cell killing, especially with antitumor alkylating agents, is maintained at higher drug doses. Several clinical trials employing two intensifications are underway. Using the tumor-cell survival assay, animals bearing the FSaII fibrosarcoma were treated with single doses of various chemotherapeutic agents once or twice with a 3- or 7-day interval between the drugs. Isobologram methodology was used to determine if the sequential treatment regimens resulted in subadditive, additive or greater-than-additive tumor-cell killing. When melphalan was followed 3 or 7 days later by a second dose of melphalan there was evidence of resistance to the second dose of melphalan as indicated by subadditive tumor-cell killing. Melphalan followed 3 days later by cyclophosphamide (300 mg/kg) produced greater-than-additive tumor-cell killing, however, when the interval was 7 days the resulting tumor-cell killing was subadditive. Melphalan followed 3 or 7 days later by thiotepa or carboplatin produced subadditive-to-additive tumor-cell killing. Adriamycin followed 3 days later by melphalan, cyclophosphamide, thiotepa, or carboplatin resulted in subadditive-to-additive tumor-cell killing by the combinations. These results indicate that sequential drug-intensive treatments may not optimize tumor-cell killing in vivo.
Holden
S A
SA
Teicher
B A
BA
Ayash
L J
LJ
Frei
E
E
D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D016190:Carboplatin / Q000008:administration & dosage; D003520:Cyclophosphamide / Q000008:administration & dosage; D004317:Doxorubicin / Q000008:administration & dosage; D004334:Drug Administration Schedule; D005354:Fibrosarcoma / Q000188:drug therapy*; D008297:Male; D008558:Melphalan / Q000008:administration & dosage; D051379:Mice; D008809:Mice, Inbred C3H; D013852:Thiotepa / Q000008:administration & dosage
D004317:Doxorubicin; D003520:Cyclophosphamide; D013852:Thiotepa; D016190:Carboplatin; D008558:Melphalan