Computerized Quantitation of Synergism and Antagonism of Taxol, Topotecan, and Cisplatin Against Human Teratocarcinoma Cell Growth: a Rational Approach to Clinical Protocol Design

Chou, Ting‐Chao; Motzer, Robert J.; Tong, Youzhi; Bosl, George J.

doi:10.1093/jnci/86.20.1517

Cited by 469 publications

(323 citation statements)

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“…Cells were therefore exposed to (i) SN-38 alone for 6 h, FU alone for 24 h, (ii) the simultaneous combination of the two drugs (SN-38 and FU for 6 h followed by FU for 18 h) or (iii) both sequential combinations of the two drugs (SN-38 for 6 h and FU for 24 h and vice versa). The CI isobologram equation was used for the analysis of the interaction between SN-38 and FU (Chou and Talalay, 1984;Chou et al, 1994). Figure 1A illustrates the results obtained after exposure of HT-29 cells (i) to increasing concentrations of FU alone (10 À4 À100 mM) or (ii) to the combination of EC 30 SN-38 (0.11 mM) and increasing concentrations of FU using both sequences or after concomitant exposure to EC 30 SN-38 and increasing concentrations of FU.…”

Section: Resultsmentioning

confidence: 99%

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Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

et al. 2006

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Several schedules of 5-fluorouracil (FU) and irinotecan (IRI) have been shown to improve overall survival in advanced colorectal cancer (CRC). Preclinical evidence suggests that the sequential administration of IRI and FU produces synergistic activity, although their clinical use has not been fully optimised. We investigated the interaction between short-term exposure to SN-38, the active metabolite of IRI, and prolonged exposure to FU in human CRC HT-29 cells and observed that the synergism of action between the two agents can be increased by extending the time of cell exposure to FU and reducing the interval between administration of the two agents. Based on these findings, we performed a phase I trial in 25 advanced CRC patients using a modified IRI/FU regimen as first-line therapy and evaluated three dose levels of IRI (150 -300 mg/m 2 ) and two of continuous infusion of FU (800 -1000 mg/m 2 ) in a 3-weekly schedule. The most severe grade III -IV toxicities were neutropoenia in four cycles and diarrhoea in three. One patient achieved complete response (4%), 12 a partial response (48%), the overall response rate was 52% (720, 95% CI); seven of 25 patients had stable disease (28%), the overall disease control was 80% (716, 95% CI). This modified IRI/FU schedule is feasible and exhibits potentially interesting clinical activity.

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Section: Resultsmentioning

confidence: 99%

“…Combination analysis was performed using the method described by Chou et al (Chou and Talalay, 1984;Chou et al, 1994). The influence of the two drugs on the combination was evaluated by comparing the sequential assay with assays involving the two drugs simultaneously or alone.…”

Section: Analysis Of Combination Effectsmentioning

confidence: 99%

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

et al. 2006

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“…The compound interactions were calculated by multiple drug effect analysis and were performed by the median equation principle according to the methodology described by Chou and Talalayb (1984). The combination index (CI) was calculated by the Chou et al equation (Chou and Talalayb, 1984;Chou et al, 1994), which takes into account both the potency and the shape of the dose -effect curve. Each CI was calculated with CalcuSyn software (Biosoft, UK) from the mean affected fraction at each drug ratio concentration.…”

Section: Cell-proliferation Assays and Combination Studiesmentioning

confidence: 99%

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

Arts¹,

Angibaud²,

Marien³

et al. 2007

Br J Cancer

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R306465 is a novel hydroxamate-based histone deacetylase (HDAC) inhibitor with broad-spectrum antitumour activity against solid and haematological malignancies in preclinical models. R306465 was found to be a potent inhibitor of HDAC1 and -8 (class I) in vitro. It rapidly induced histone 3 (H3) acetylation and strongly upregulated expression of p21 waf1,cip1 , a downstream component of HDAC1 signalling, in A2780 ovarian carcinoma cells. R306465 showed class I HDAC isotype selectivity as evidenced by poor inhibition of HDAC6 (class IIb) confirmed by the absence of downregulation of Hsp90 chaperone c-raf protein expression and tubulin acetylation. This distinguished it from other HDAC inhibitors currently in clinical development that were either more potent towards HDAC6 (e.g. vorinostat) or had a broader HDAC inhibition spectrum (e.g. panobinostat). R306465 potently inhibited cell proliferation of all main solid tumour indications, including ovarian, lung, colon, breast and prostate cancer cell lines, with IC 50 values ranging from 30 to 300 nM. Haematological cell lines, including acute lymphoblastic leukaemia, acute myeloid leukaemia, chronic lymphoblastic leukaemia, chronic myeloid leukaemia, lymphoma and myeloma, were potently inhibited at a similar concentration range. R306465 induced apoptosis and inhibited angiogenesis in cell-based assays and had potent oral in vivo antitumoral activity in xenograft models. Once-daily oral administration of R306465 at well-tolerated doses inhibited the growth of A2780 ovarian, H460 lung and HCT116 colon carcinomas in immunodeficient mice. The high activity of R306465 in cell-based assays and in vivo after oral administration makes R306465 a promising novel antitumoral agent with potential applicability in a broad spectrum of human malignancies.

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“…An algorithm was used to calculate whether these drugs were synergistic. 23 Two drugs are considered synergistic if the surviving fraction of the combination is lower than the product of the surviving fractions for each agent alone. Based on this criterium, FTI and microtubule-stabilizing agents were synergistic in inhibiting the growth of DU145 human prostate cancer cells.…”

Section: Synergistic Effect Of Epothilones and Farnesyl Transferase Imentioning

confidence: 99%

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

Sepp‐Lorenzino

Balog

et al. 1999

Prostate Cancer Prostatic Dis

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Epothilones are a new class of natural products that bind to tubulin and prevent the depolymerization of microtubules, although they have no structural similarity to paclitaxel. Taxanes are only marginally effective in the treatment of disseminated prostate cancer, although they may have useful activity when administered in combination with estramustine. Unlike paclitaxel, epothilones are not substrates for P-glycoprotein and are active in multidrug resistant cells. Epothilones A and B (EA, EB) have recently been synthesized in toto. In this report, we examine the effects of synthetic epothilones and their desoxy derivatives, as well as paclitaxel, on prostate cancer cell lines. EB was the most active of these compounds in tissue culture (IC 50 : 50 ± 75 pM), four to ten-fold more potent than paclitaxel. EA and the desoxyderivatives of EA and EB (dEA, dEB) were also active, but less potent than EB. Each of these compounds causes mitotic block followed by apoptotic cell death. The relative potencies for cell cycle arrest and cytotoxicity directly correlate with the ability of the drugs to bind microtubules, stabilize mitotic spindles and induce the formation of interphase microtubule bundles. Therefore, synthetic epothilones are potent inhibitors of prostate cancer cell lines and work in a fashion similar to paclitaxel. Recently, we showed that farnesyl transferase inhibitors sensitize tumor cells to paclitaxelinduced mitotic arrest. We now have extended these observations to show that paclitaxel and the epothilones synergize with FTI to arrest the growth of prostate cancer cells. Moreover, this occurs in DU145, a cell line that is not particularly sensitive to the FTI. The combination of FTI and epothilone represent a new potential clinical strategy for the treatment of advanced prostatic cancer.

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Computerized Quantitation of Synergism and Antagonism of Taxol, Topotecan, and Cisplatin Against Human Teratocarcinoma Cell Growth: a Rational Approach to Clinical Protocol Design

Cited by 469 publications

References 1 publication

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

Schedule-dependent activity of 5-fluorouracil and irinotecan combination in the treatment of human colorectal cancer: in vitro evidence and a phase I dose-escalating clinical trial

R306465 is a novel potent inhibitor of class I histone deacetylases with broad-spectrum antitumoral activity against solid and haematological malignancies

The microtubule-stabilizing agents epothilones A and B and their desoxy-derivatives induce mitotic arrest and apoptosis in human prostate cancer cells

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