Influence of scheduling on two-drug combinations of alkylating agents in vivo.
The effects of schedule and sequence on the survival of EMT6 tumor cell and bone marrow (CFU-GM) obtained after treatment using combinations of cyclophosphamide (CTX) and thiotEPA or melphalan (L-PAM) were examined and analyzed by isobologram methodology. On a single-injection schedule, when CTX and thio-tEPA were given simultaneously or thiotEPA was given prior to CTX, the result was slightly greater than additive tumor-cell kill. However, when CTX preceded thiotEPA by 4 h, there was less than additive cell kill. When the interval between the administration of the two drugs was 8 h, both sequences of the drugs produced greater than additive tumor-cell kill. Simultaneous administration of CTX and thiotEPA on a multiple-injection schedule resulted in sub-additive tumor-cell kill. On the multiple-injection schedule, extending the interval between injections of CTX and thiotEPA to 4 and 8 h resulted in increasing tumor-cell kill. With the 4- and 8-h intervals, no significant sequence-dependent difference in tumor-cell kill was obtained. The results of CTX and L-PAM combinations paralleled those of CTX and thiotEPA. Bone marrow (CFU-GM) survival was used as a representative normal tissue with which to compare tumor-cell survival after each treatment to obtain a measure of therapeutic effect. The trends for the ratios of bone marrow: tumor cell survival were the same for the treatment sequences of CTX with thiotEPA or L-PAM; however, greater magnitudes of differential tumor-cell kill were obtained with CTX L-PAM combinations. Using this measure, the greatest therapeutic effectiveness was seen with single-dose L-PAM or thio-tEPA followed 4 h later by CTX and with CTX given as a single or as multiple doses followed 8 h later by L-PAM or thiotEPA. Such data from tumor-model systems may be useful in the development of more effective alkylating agent regimens for use in the clinic.
Teicher
B A
BA
Dana-Farber Cancer Institute, Boston MA 02115.
Holden
S A
SA
Jones
S M
SM
Eder
J P
JP
Herman
T S
TS
D000477:Alkylating Agents / Q000008:administration & dosage* / Q000633:toxicity; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use* / Q000633:toxicity; D001853:Bone Marrow / Q000187:drug effects / Q000473:pathology; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D005260:Female; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D008558:Melphalan / Q000008:administration & dosage / Q000633:toxicity; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D013852:Thiotepa / Q000008:administration & dosage / Q000633:toxicity; D013997:Time Factors
D000477:Alkylating Agents; D003520:Cyclophosphamide; D013852:Thiotepa; D008558:Melphalan