Abstract
A panel of six 'wild type' and three VP-16 resistant small cell lung cancer (SCLC) cell lines is used to evaluate to what extent in vitro sensitivity testing using a clonogenic assay can contribute to combine cytotoxic drugs to regimens with improved efficacy against SCLC. The resistant lines include (a) H69/DAU4, which is classical multidrug resistant (MDR) with a P-glycoprotein efflux pump (b) NYH/VM, which exhibits an altered topoisomerase II (topo II) activity and (c) H69/VP, which is cross-resistant to vincristine, exhibits a reduced drug accumulation as H69/DAU4 but is without P-glycoprotein. 19 anticancer agents were compared in the panel. The MDR lines demonstrated, as expected, cross-resistance to all topo II drugs, but also different patterns of collateral sensitivity to BCNU, cisplatin, ara-C, hydroxyurea, and to the topo I inhibitor camptothecin. The complete panel of nine cell lines clearly demonstrated diverse sensitivity patterns to drugs with different modes of action. Correlation analysis showed high correlation coefficients (CC) among drug analogues (e.g. VP-16/VM-26 0.99, vincristine/vindesine 0.89), and between drugs with similar mechanisms of action (e.g. BCNU/Cisplatin 0.89, VP-16/Doxorubicin 0.92), whereas different drug classes demonstrated low or even negative CC (e.g. BCNU/VP-16 -0.21). When the CC of the 19 drug patterns to VP-16 were plotted against the CC to BCNU, clustering was observed between drugs acting on microtubules, on topo II, alkylating agents, and antimetabolites. In this plot, camptothecin and ara-C patterns were promising by virtue of their lack of cross-resistance to alkylating agents and topo II drugs. Thus, the differential cytotoxicity patterns on this panel of cells can (1) give information about drug mechanism of action, (2) enable the selection and combination of non-cross-resistant drugs, and (3) show where new drugs 'fit in' among established agents.
Highlights
In the present investigations we evaluated the sensitivity patterns to 19 different anticancer agents on six wild type small cell lung cancer (SCLC) cell lines and on the three multidrug resistant (MDR) cell lines H69/DAU4, NYH/VM, and H69/VP representing classical P-glycoprotein MDR, altered topoisomerase II MDR, and a less defined MDR mechanism exhibiting a reduced drug accumulation, respectively
The cytotoxicity of the 19 anticancer agents was determined in a clonogenic assay as described in Materials and methods
Both resistant sublines of H69 exhibit collateral sensitivity to BCNU and Ara-C. Not statistically significant both lines seem collaterally sensitive to cisplatin (CIS), camptothecin (CAM), and hydroxyurea (HYD)
Summary
Drugs [3H] Daunorubicin (3.1 Ci/mmol) was obtained from DuPont NEN. Melphalan (MEL) [Wellcome] was dissolved in hydrochloric acid with ethanol and further diluted in propyleneglycol phosphate buffer, m-AMSA (MAM) [Parke-Davis] was delivered in N,N-dimetylacetamid solution and further diluted in acid lactose, and Ara-C (ARAC) (cytosine arabinoside) [Upjohn] was dissolved in benzyl alcohol, all the solvents used were dispensed by the producers. Doxorubicin (DOX) [Farmitalia Carlo Erba], aclarubicin (ACLA) and bleomycin (BLEO) [Lundbeck], hydroxyurea (HYD) [kindly supplied by Bristol-Myers Squibb], 4'-deoxy-4'-iododoxorubicin (IOD) (lododoxorubicin) [kindly supplied from Farmitalia Carlo Erba], mitomycin C (MTC) [Kyowa], and vincristine [Lilly] (VCR) were dissolved in sterile water. Vindesine (VDS) [Lilly] was dissolved in isotonic sodium chloride. Camptothecin (CAM) [Sigma] was dissolved in DMSO. BCNU [Bristol-Myers Squibb] was dissolved in 10% v/v ethanol in sterile water. Mitoxantrone (MIT) [Lederle], VP16 (etoposide) [Bristol-Myers Squibb], VM-26 (teniposide) [Bristol-Myers Squibb], methotrexate (MTX) [Lederle], 5fluorouracil (SFU) [Roche] and cisplatin (CIS) [Bristol-Myers
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