Abstract
Doxorubicin (DXR) has a positive inoculum effect and penetrates poorly into the core of multicellular tumour spheroids (MTS). Cis-platin (DDP) displays neither of these characteristics. We evaluated whether combining these 2 agents would influence the cell kill effect at a tumour mass level. MTS were produced from a PC-10 squamous lung carcinoma cell line. MTS were exposed to either drug first for 1 h with different intervals between exposure. Cells were then trypsinized to a single cell suspension and subjected to clonogenic assay. Combination effects were analyzed by median effect plot analysis. The more MTS ml-1 medium, the lower the cell kill effect of DXR. Simultaneous exposure to the 2 drugs was synergistic. DXR exposure first followed by DDP was less efficacious than, or the same as, the simultaneous exposure. In contrast, DDP followed by DXR was more efficacious with the best cell kill at a 1 h interval between each drug. This phenomenon was observed even at non-toxic doses of DDP. The fluorescent microscopic study of DXR indicated that prior exposure of MTS to DDP resulted in increased DXR penetration into the MTS core leading to heightened synergism with this sequence. These data suggest that the proper combination of DXR plus DDP should be in sequence with DDP first. Clinical, toxicological and pharmacological trials of DDP administration first, followed by DXR, are warranted.
Highlights
We introduced a combination of these 2 agents, termed A & P (Vogl et al, 1976), which has become the basis, by adding more drugs, for the treatment of patients with ovarian cancer, small cell lung cancer and other neoplasms
For DXR-induced cell lethality, the higher the density of multicellular tumour spheroids (MTS), the lesser the cell kill effects and dose-response curves of DXR progressively flattened at high drug concentrations
DDP gave entirely different dose-effect curves; cell survival curves for high MTS density and low density overlapped each other and there was progressively increasing cell kill at increasing doses
Summary
Human tumour cell linePC-10 squamous lung carcinoma cell line was used in these experiments (Kinjo et al, 1979). Cells were maintained as a monolayer in RPMI-1640 medium (GIBCO, Grand Island, NY), supplemented with 10% (v/v) heat-inactivated foetal bovine serum (FBS) (Gibco) at 37"C in a 5% CO2/95% humidified air atmosphere. These cells were subcultured after trypsinization with 0.2% trypsin (Type III from bovine pancreas, Sigma, St Louis, MD) and 0.01% EDTA in Hank's balanced salt solution (HBSS) (Gibco). MTS were developed by a liquid overlay culture technique (Yuhas et al, 1977), as described previously (Kohno et al, 1987). Aliquots of I x 105 cells in 10ml of complete culture medium were placed in 100mm plastic Petri dishes Received 21 January 1988; and in revised form, 19 May 1988
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