Autologous Bone Marrow Transplantation - Blog Science Connections

Clinical Intensification Regimens forABMT 577
should cross to other alkylating agents. Thus low-level or partial crossresistance
should be common, which in fact is the case, based on the
aforementioned studies.
ANALYSIS OF IN VITRO MULTILOG KILLING CURVES
In general, sensitivity and cross-resistance are measured by determining
the 1C 50
over a 1-log dose range. This provides information that may be
relevant to remission induction in the clinic but could be misleading with
respect to multilog cell kill, a property essential to cure. Figure 3 presents
multilog cell-kill curves for three alkylating agents and five representative
human solid tumor cell lines. Note that phenylalanine mustard (PAM) and
cisplatin maintain linearity with respect to log kill in some tumors, while in
others they become less effective with increasing dose. The latter presumably
represents heterogeneity with respect to drug resistance (9). Skipper and
colleagues have determined that this property may be crucial to the effects of
initial treatment. Thus they have found on the basis of preclinical in vivo
studies that where 10 2
tumor cells are resistant, tumor regression will not
occur; if 10 4 are resistant, moderate response may be achieved; if 10~ 6 are
resistant, a major antitumor effect occurs (10). On this basis, we divided the
curves in Figure 3 accordingly, with 4+ representing a straight-line effect, and
1 to 2+ a plateau at the level of 1 - 2 logs. These data are presented semiquan-
Drug Concentration, uM
Figure 3. Relative effects of three alkylating agents, PAM (phenylalanine mustard),
cyclophosphamide (CP), and BCNU (carmustine), on cell lines of head and neck, breast,
melanoma, lung non-small cell, and lung small cell cancers.