Influence of scheduling on two-drug combinations of alkylating agents in vivo

Cancer Chemother Pharmacol. 1989;25(3):161-6. doi: 10.1007/BF00689576.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Alkylating Agents / administration & dosage*
  • Alkylating Agents / toxicity
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / therapeutic use*
  • Antineoplastic Combined Chemotherapy Protocols / toxicity
  • Bone Marrow / drug effects
  • Bone Marrow / pathology
  • Cell Survival / drug effects
  • Cyclophosphamide / administration & dosage
  • Cyclophosphamide / toxicity
  • Dose-Response Relationship, Drug
  • Drug Screening Assays, Antitumor
  • Female
  • Mammary Neoplasms, Experimental / drug therapy
  • Mammary Neoplasms, Experimental / pathology
  • Melphalan / administration & dosage
  • Melphalan / toxicity
  • Mice
  • Mice, Inbred BALB C
  • Neoplasm Transplantation
  • Thiotepa / administration & dosage
  • Thiotepa / toxicity
  • Time Factors


  • Alkylating Agents
  • Cyclophosphamide
  • Thiotepa
  • Melphalan