Combination chemotherapy in advanced gastrointestinal cancers: ex vivo sensitivity to gemcitabine and mitomycin C

Whitehouse, Pauline; Mercer, Stuart; Knight, Louise A.; Nicolantonio, Federica Di; O’Callaghan, Ann; Cree, Ian A.

doi:10.1038/sj.bjc.6601403

Cited by 8 publications

(4 citation statements)

References 41 publications

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“…In addition, CTP, GTP and UTP demonstrated similar increases at two concentrations of dFdC (Table 1). The effects of dFdC on ribonucleotide triphosphates have already been reported and possibly related with the cytostatic effect of gemcitabine2526. Of note, the inhibition of ribonucleotide reductase by dFdC after 24 h of incubation did not significantly increase the levels of ribonucleotide diphosphates, except for adenosine diphosphate (ADP).…”

Section: Resultsmentioning

confidence: 90%

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

Guo

Chen

Lam

et al. 2016

Sci Rep

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In this study, we investigated the dosage effect of gemcitabine, an inhibitor of ribonucleotide reductase (RR), on cellular levels of ribonucleotides and deoxyribonucleotides using high performance liquid chromatography-electrospray ionization tandem mass spectrometric method. As anticipated, after 4-h incubation of non-small cell lung cancer (A549) cells with gemcitabine at 0.5 and 2 μM, there were consistent reductions in levels of deoxyribonucleoside diphosphates (dNDP) and their corresponding deoxyribonucleoside triphosphates (dNTP). However, after 24-h exposure to 0.5 μM gemcitabine, the amounts of dNTP were increased by about 3 fold, whereas cells after 24-h 2 μM gemcitabine treatment exhibited deoxycytidine diphosphate (dCDP), deoxyadenosine diphosphate (dADP) and deoxyguanosine diphosphate (dGDP) levels less than 50% of control values, with deoxycytidine triphosphate (dCTP) and deoxyguanosine triphosphate (dGTP) returning to the control level. Using cell cycle analysis, we found that 24-h incubation at 0.5 μM gemcitabine resulted in a significant increase in S phase arrest, while 2 μM treatment increased G0/G1 population. Our data demonstrated the correlation between the level of RR and the increased levels of dNTPs in the group of 0.5 μM treatment for 24-h with a markedly reduced level of dFdCTP. Accordingly, we proposed that the dosage of dFdC could determine the arrested phase of cell cycle, in turn affecting the recovery of dNTPs pools.

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Section: Resultsmentioning

confidence: 90%

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

Guo

Chen

Lam

et al. 2016

Sci Rep

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“…Further statistical tests (SPSS Software) were performed when direct comparisons were necessary: the Wilcoxon rank-sum test was used to compare paired series. Combination effects were assessed using Chou's method (Chou and Talalay, 1984), as previously used with the ATP-TCA (Whitehouse et al, 2003b). The combination index (CI) was determined at 90% cell death, and was defined as follows: where CI A+B = CI for a fixed effect (F = 90%) for the combination of cytotoxic A and cytotoxic B; D A/A+B or D B/A+B = concentration of cytotoxic A or B in the combination A + B; D A or D B = concentration of cytotoxic A or B alone; alpha = parameter with value 0 when A and B are mutually exclusive, and 1 when A and B are mutually nonexclusive.…”

Section: Discussionmentioning

confidence: 99%

In vitro chemosensitivity in breast cancer using ATP-tumor chemosensitivity assay

Ning

Zhu

et al. 2009

Arch. Pharm. Res.

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Chemotherapy for breast cancer is given on the basis of empirical information from clinical trials, an approach which falls to take into account the known heterogeneity of chemosensitivity between patients. This study aimed to demonstrate the degree of heterogeneity of chemosensitivity in breast cancers. In this study, we examined the heterogeneity of chemosensitivity in breast cancer specimens (n = 50) using an ex vivo ATP-tumor chemosensitivity assay (ATP-TCA). Assay evaluability was 92% in surgical biopsies or pleural aspirates. A variety of chemosensitivity agents were tested. We found that the most active single agent tested was paclitaxel, to which 65.9% of samples were sensitive. Combinations of agents also showed more strong sensitivity cases. The Adriamycin+5-FU demonstrated a strong sensitivity in 23 of 43 (52.3%) of samples. Adriamycin+paclitaxel was more effective, with strong sensitivity in 37 of 43 cases tested (86.0%). There was a marked heterogeneity of chemosensitivity in breast cancer. Chemosensitivity testing may provide a practical method of testing new regimens before clinical trials in breast cancer patients.

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“…Further statistical tests (SPSS Software, IL, USA) were performed when direct comparisons were necessary: the Wilcoxon rank-sum test was used to compare paired series. Combination effects were assessed using Chou's method [16] , as previously used with the ATP-TCA [17] . The combination index (CI) was determined at 90% cell death, and was …”

Section: Methodsmentioning

confidence: 99%

Heterogeneity of chemosensitivity in esophageal cancer using ATP-tumor chemosensitivity assay

Ling

et al. 2012

Acta Pharmacol Sin

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Aim: Current chemotherapy for esophageal cancer is conducted on the basis of empirical information from clinical trials, which fails to take into account the known heterogeneity of chemosensitivity between patients. This study was aimed to demonstrate the degree of heterogeneity of chemosensitivity in esophageal cancers. Methods: A total of 42 esophageal cancer specimens were collected. The heterogeneity of chemosensitivity in esophageal cancer specimens was examined using an ex vivo ATP-tumor chemosensitivity assay (ATP-TCA). Results: Thirty eight specimens produced evaluable results (90.5%). The most active single agent tested was nedaplatin, to which 28.9% of samples were sensitive. Combinations of chemotherapy agents exhibited much higher sensitivity: cisplatin+paclitaxel was sensitive in 16 of 38 (42.1%) of samples, while nedaplatin+paclitaxel was more effective, which was sensitive in 20 of 38 cases (52.6%). Conclusion: There was a marked heterogeneity of chemosensitivity in esophageal cancer. Chemosensitivity testing may provide a practical method for testing new regimens before clinical trials in esophageal cancer patients.

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Combination chemotherapy in advanced gastrointestinal cancers: ex vivo sensitivity to gemcitabine and mitomycin C

Cited by 8 publications

References 41 publications

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

Profiling ribonucleotide and deoxyribonucleotide pools perturbed by gemcitabine in human non-small cell lung cancer cells

In vitro chemosensitivity in breast cancer using ATP-tumor chemosensitivity assay

Heterogeneity of chemosensitivity in esophageal cancer using ATP-tumor chemosensitivity assay

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