High dose, multiple
alkylating agent chemotherapy is being employed in conjunction with autologous marrow
transplantation in the clinic. We have investigated the scheduling of several alkylating drugs in an effort to optimize their antitumor effects. In vitro modeling of "continuous" (up to 72 h) versus "bolus" (1 h) exposure in MCF-7 cells showed that for N,N',N"-
triethylenethiophosphoramide (
thiotEPA),
cis-diamminedichloroplatinum(II) (CDDP),
4-hydroperoxycyclophosphamide,
carboplatin, and
L-phenylalanine mustard (
L-PAM) "continuous" exposure yielded essentially the same killing kinetics as "bolus" exposure. For
N,N'-bis(2-chloroethyl)-N-nitrosourea (
BCNU), however, even with fresh
drug additions every 30 min, "bolus" exposure produced superior cytotoxicity. In vivo modeling of "continuous" (three i.p.
injections over 9 h) versus "bolus" (single dose) administration of the
alkylating agents cyclophosphamide,
BCNU,
thiotEPA,
melphalan, CDDP, and
carboplatin was conducted in mice bearing EMT6
tumors, and
tumor cell killing as measured by
tumor cell survival in vitro was compared with killing of bone marrow (CFU-GM) measured in culture as a representative sensitive normal tissue. With
cyclophosphamide there was a considerable increase in the therapeutic index (killing of
tumor cells/killing of CFU-GMs) when the same total dose of
drug was administered in multiple
injections versus a single injection. For
BCNU and
thiotEPA, smaller increases in therapeutic index were observed. With
L-PAM and CDDP, some advantage to multiple versus single dose administration was observed, and for
carboplatin a decrease in the therapeutic index was seen. In conclusion, for all six
alkylating agents examined, the multiple dose schedule was at least as effective against the
tumor as the single dose schedule at all dose levels.