Autologous Bone Marrow Transplantation - Blog Science Connections

Clinical Intensification Regimens for ABMT
Table 3. Resistance Ratios 3
to Various Antineoplastic Agents
Cell
Agent
Line ADR 6 ADR° VCR 6 FU" MTX 6 MTX C
Raji/BCNU 0.3 — 0.7 1.0 1.4 —
Raji/HN 2 0.3 0.5 0.7 3.4 1.2 2.5
Raji/CP 0.2 0.5 0.2 1.9 1.6 1.5
SCC-25/CP 0.6 0.4 0.9 0.6 23.8 7.3
'Resistance ratio = IC 50 of resistant iine/IC 50 of parental line. The /Cs 0s
(micromolar) for the Raji parental line were: ADR b , 0.66; ADR°, 0.04; VCR , 0.11; Ft/,
44; MTX b , 41; and MTX C , 0.022. The IC 50s (micromolar) for the SCC-25 parental line
were: ADR b , 2.8; ADR°, 0.013; VCR b , 0.21; FU d , 52; MTx", 34; and MTX C , 0.006.
Drug exposure
for 30 min.
°Drug exposure continuous.
d
Drug exposure for 24 fir.
Abbreviations: ADR, Adriamycin; VCR, vincristine; FU, 5-fluorouracil; MTX,
methotrexate; HN 2, nitrogen mustard; CP, cyclophosphamide.
clone showed substantial cross-resistance to methotrexate. As a generalization,
however, alkylating-agent resistance did not cross to other antitumor
agents.
Developing studies with respect to the biochemistry of alkylating-agent
resistance indicate that a variety of mechanisms of resistance may be
involved, some of which are specific for a given alkylating agent (Table 4).
Resistance is often multifactorial. Teicher et al. have found, for example, that
resistance to cisplatin of a squamous cell carcinoma of the head and neck cell
line was due to: a decrease in plasma membrane transport, an increase in
protein sulfhydryls in the cytosol (and some cross-resistance to cadmium), an
increase in glutathione reductase, and possibly an increase in DN A repair (8).
Some of these mechanisms should be unique to cisplatin, whereas others
Table 4. Documented Mechanisms of Alkylating Agent Resistance
D r u
9 Resistance Mechanism
Nitrogen mustard (HN 2 )
Melphalan
Nitrosoureas
Cyclophosphamide
Cisplatin
Transport reduction
Glutathione reductase increase
DNA repair increase
Transport reduction
Glutathione increase
DNA repair increase
Aldehyde dehydrogenase increase
Transport reduction
Glutathione reductase increase
Protein-sulfhydryl increase