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Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment.

Wang E, Bussom S, Chen J, Quinn C, Bedognetti D, Lam W, Guan F, Jiang Z, Mark Y, Zhao Y, Stroncek DF, White J, Marincola FM, Cheng YC - BMC Med Genomics (2011)

Bottom Line: Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures.PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy.Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

View Article: PubMed Central - HTML - PubMed

Affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT

Background: Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

Methods: Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors.

Results: We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection.

Conclusions: PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.

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Related in: MedlinePlus

Effect of PHY906 and/or CPT-11 on tumor, spleen and liver. (a) Effect of PHY906 and/or CPT-11 on tumor size 72 hours after the initiation of treatment. The p-values refer to unpaired Student t test between groups. (b) Multidimensional scaling (MDS) based on the complete filtered data set including 18,549 transcripts demonstrating in Euclidian space distances among tumor, liver and spleen of animals treated with PBS. (c) Unsupervised, self-organizing clustering based on transcripts that passed for each tissue studied a filter requirement of 80% presence and at least one experiment with a ratio above 4 out of 18,549 that originally passed the less stringent filter (experimental clustering based on Kendal's Tau regression model, tumor = 2, 635 transcripts, spleen = 2,079 transcripts, liver = 1,059). (d) Self-organizing clustering based on 700 genes out of 1,132 tumor genes differentially expressed among the four treatment groups (F test, p-value cutoff < 0.001) that passed a filter of 80% presence and a log ratio ≥ 3 in at least one experiment. Highlighted in yellow is the area of the heat map were enhancement of the CPT-11 effects by the combination CPT-11+PHY906.
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Figure 1: Effect of PHY906 and/or CPT-11 on tumor, spleen and liver. (a) Effect of PHY906 and/or CPT-11 on tumor size 72 hours after the initiation of treatment. The p-values refer to unpaired Student t test between groups. (b) Multidimensional scaling (MDS) based on the complete filtered data set including 18,549 transcripts demonstrating in Euclidian space distances among tumor, liver and spleen of animals treated with PBS. (c) Unsupervised, self-organizing clustering based on transcripts that passed for each tissue studied a filter requirement of 80% presence and at least one experiment with a ratio above 4 out of 18,549 that originally passed the less stringent filter (experimental clustering based on Kendal's Tau regression model, tumor = 2, 635 transcripts, spleen = 2,079 transcripts, liver = 1,059). (d) Self-organizing clustering based on 700 genes out of 1,132 tumor genes differentially expressed among the four treatment groups (F test, p-value cutoff < 0.001) that passed a filter of 80% presence and a log ratio ≥ 3 in at least one experiment. Highlighted in yellow is the area of the heat map were enhancement of the CPT-11 effects by the combination CPT-11+PHY906.

Mentions: Forty BDF-1 mice, each bearing a colon 38 tumor, were divided into the following four treatment groups: Phosphate Buffered Saline (PBS, control), PHY906 (500 mg/Kg, twice a day for 72 hours), CPT-11 (Camptosar®, 360 mg/kg), or = PHY906(500 mg/Kg), followed 30 minutes later by a single injection of CPT-11 (360 mg/kg) with continued twice a day dosing of PHY906 (500 mg/Kg) for 72 hours. Tumors were measured 72 hours after treatment (Figure 1a) and then removed. As expected [6], PHY906 enhanced the anti-tumor activity of CPT-11 although alone it had no effect on tumor growth. These early effects resulted in better long term reduction of tumor growth compared to CPT-11 treatment alone up to the 14th day from the beginning of treatment [12]. No differences in animal body weight were observed between the CPT-11 and the CPT-11 plus PHY906 groups.


Interaction of a traditional Chinese Medicine (PHY906) and CPT-11 on the inflammatory process in the tumor microenvironment.

Wang E, Bussom S, Chen J, Quinn C, Bedognetti D, Lam W, Guan F, Jiang Z, Mark Y, Zhao Y, Stroncek DF, White J, Marincola FM, Cheng YC - BMC Med Genomics (2011)

Effect of PHY906 and/or CPT-11 on tumor, spleen and liver. (a) Effect of PHY906 and/or CPT-11 on tumor size 72 hours after the initiation of treatment. The p-values refer to unpaired Student t test between groups. (b) Multidimensional scaling (MDS) based on the complete filtered data set including 18,549 transcripts demonstrating in Euclidian space distances among tumor, liver and spleen of animals treated with PBS. (c) Unsupervised, self-organizing clustering based on transcripts that passed for each tissue studied a filter requirement of 80% presence and at least one experiment with a ratio above 4 out of 18,549 that originally passed the less stringent filter (experimental clustering based on Kendal's Tau regression model, tumor = 2, 635 transcripts, spleen = 2,079 transcripts, liver = 1,059). (d) Self-organizing clustering based on 700 genes out of 1,132 tumor genes differentially expressed among the four treatment groups (F test, p-value cutoff < 0.001) that passed a filter of 80% presence and a log ratio ≥ 3 in at least one experiment. Highlighted in yellow is the area of the heat map were enhancement of the CPT-11 effects by the combination CPT-11+PHY906.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3117677&req=5

Figure 1: Effect of PHY906 and/or CPT-11 on tumor, spleen and liver. (a) Effect of PHY906 and/or CPT-11 on tumor size 72 hours after the initiation of treatment. The p-values refer to unpaired Student t test between groups. (b) Multidimensional scaling (MDS) based on the complete filtered data set including 18,549 transcripts demonstrating in Euclidian space distances among tumor, liver and spleen of animals treated with PBS. (c) Unsupervised, self-organizing clustering based on transcripts that passed for each tissue studied a filter requirement of 80% presence and at least one experiment with a ratio above 4 out of 18,549 that originally passed the less stringent filter (experimental clustering based on Kendal's Tau regression model, tumor = 2, 635 transcripts, spleen = 2,079 transcripts, liver = 1,059). (d) Self-organizing clustering based on 700 genes out of 1,132 tumor genes differentially expressed among the four treatment groups (F test, p-value cutoff < 0.001) that passed a filter of 80% presence and a log ratio ≥ 3 in at least one experiment. Highlighted in yellow is the area of the heat map were enhancement of the CPT-11 effects by the combination CPT-11+PHY906.
Mentions: Forty BDF-1 mice, each bearing a colon 38 tumor, were divided into the following four treatment groups: Phosphate Buffered Saline (PBS, control), PHY906 (500 mg/Kg, twice a day for 72 hours), CPT-11 (Camptosar®, 360 mg/kg), or = PHY906(500 mg/Kg), followed 30 minutes later by a single injection of CPT-11 (360 mg/kg) with continued twice a day dosing of PHY906 (500 mg/Kg) for 72 hours. Tumors were measured 72 hours after treatment (Figure 1a) and then removed. As expected [6], PHY906 enhanced the anti-tumor activity of CPT-11 although alone it had no effect on tumor growth. These early effects resulted in better long term reduction of tumor growth compared to CPT-11 treatment alone up to the 14th day from the beginning of treatment [12]. No differences in animal body weight were observed between the CPT-11 and the CPT-11 plus PHY906 groups.

Bottom Line: Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures.PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy.Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

View Article: PubMed Central - HTML - PubMed

Affiliation: Infectious Disease and Immunogenetics Section (IDIS), Department of Transfusion Medicine, Clinical Center and trans-NIH Center for Human Immunology (CHI), National Institutes of Health, Bethesda, Maryland 20892, USA.

ABSTRACT

Background: Traditional Chinese Medicine (TCM) has been used for thousands of years to treat or prevent diseases, including cancer. Good manufacturing practices (GMP) and sophisticated product analysis (PhytomicsQC) to ensure consistency are now available allowing the assessment of its utility. Polychemical Medicines, like TCM, include chemicals with distinct tissue-dependent pharmacodynamic properties that result in tissue-specific bioactivity. Determining the mode of action of these mixtures was previously unsatisfactory; however, information rich RNA microarray technologies now allow for thorough mechanistic studies of the effects complex mixtures. PHY906 is a long used four herb TCM formula employed as an adjuvant to relieve the side effects associated with chemotherapy. Animal studies documented a decrease in global toxicity and an increase in therapeutic effectiveness of chemotherapy when combined with PHY906.

Methods: Using a systems biology approach, we studied tumor tissue to identify reasons for the enhancement of the antitumor effect of CPT-11 (CPT-11) by PHY906 in a well-characterized pre-clinical model; the administration of PHY906 and CPT-11 to female BDF-1 mice bearing subcutaneous Colon 38 tumors.

Results: We observed that 1) individually PHY906 and CPT-11 induce distinct alterations in tumor, liver and spleen; 2) PHY906 alone predominantly induces repression of transcription and immune-suppression in tumors; 3) these effects are reverted in the presence of CPT-11, with prevalent induction of pro-apoptotic and pro-inflammatory pathways that may favor tumor rejection.

Conclusions: PHY906 together with CPT-11 triggers unique changes not activated by each one alone suggesting that the combination creates a unique tissue-specific response.

Show MeSH
Related in: MedlinePlus