Autologous Bone Marrow Transplantation - Blog Science Connections

Clinical Intensification Regimens forABMT 573
appropriate to the transplant arena. We are now using this system to analyze a
number of variables, particularly those relating to effect of tumor size on
fractional kill, the effect of different drugs and different tumors, and the effect
of schedule and combination therapy on cell kill.
CROSS-RESISTANCE AMONG ALKYLATING AGENTS IN
COMBINATION CHEMOTHERAPY
Schabel and colleagues, some 7 years ago, demonstrated for LI 210
mouse leukemia that induction of resistance to a given alkylating agent
usually did not confer cross-resistance to the other alkylating agents (Table 1 )
(2). This observation, which was counterdogma at the time, was of major
significance, since it indicated that the alkylating agents, perhaps the most
important class of antitumor agent, were not "one" radiomimetic agent with
minor differences with respect to toxicity, route of administration, etc., but
rather were fundamentally different one from the other. This difference,
expressed in terms of lack of cross-resistance, could provide a major basis for
combination alkylating agent therapy. Indeed, Schabel and colleagues went
on to demonstrate that various combinations of alkylating agents were
commonly synergistic (2,3). Since such agents have steep dose-response
curves as already indicated, have myelosuppression as the dose-limiting
toxicity, and often have differing nonmyelosuppressive dose-limiting toxicities,
combining them intensively represented an attractive approach to transplant
therapy. However, before proceeding it was necessary to demonstrate their
properties, particularly the lack of cross-resistance, in human tumors.
Accordingly, alkylating agent-resistant lines of human tumors were
produced by prolonged progressive selection pressure (Fig 2). Using a
comparable protocol against a variety of human tumor cell lines, high levels
(4-5 logs) of resistance to methotrexate and resistance in excess of 600-fold
to Adriamycin can be achieved (4).
For nonalkylating agents, it is a generalization that, with appropriate
selection pressure, high levels of resistance can be achieved readily. In
Table 1. Cross-Resistance Among Alkylating Agents (LI210 Mouse Leukemia)
L1210 L1210/CPA L1210/PAM L1210/BCNU L1210/Platinum
CPA 7 a 0-1 5 7 5
PAM 6 4 0 7 5
BCNU 5 5 5 0-1 3
Platinum 5 5 5 5 0-1
Abbreviations: CPA, cyclophosphamide; PAM, phenylalanine mustard; BCNU,
carmustine; platinum, cisplatin.
"Tumor cell kill (in logs) achieved in L1210 in vivo with /_D 1 0
dose of drug.