putrescine and Colorectal Cancer studies

Research Excerpts

Excerpt	Relevance	Reference
"The development of chemoresistance to 5-fluorouracil (5-FU) is a major obstacle for sustained effective treatment of colorectal cancer (CRC), with the mechanisms being not fully understood."	7.83	Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine. ( Chen, X; Chen, Y; Hao, L; Hou, A; Li, Y; Liang, H; Luo, P; Miao, H; Ou, J; Ruan, Z; Shi, C; Wang, R; Zhang, X, 2016)
"The development of chemoresistance to 5-fluorouracil (5-FU) is a major obstacle for sustained effective treatment of colorectal cancer (CRC), with the mechanisms being not fully understood."	3.83	Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine. ( Chen, X; Chen, Y; Hao, L; Hou, A; Li, Y; Liang, H; Luo, P; Miao, H; Ou, J; Ruan, Z; Shi, C; Wang, R; Zhang, X, 2016)
"Naproxen, sulindac and salicylate, three NSAIDs (non-steroidal anti-inflammatory drugs), were cytotoxic to human colorectal cancer cells in culture."	3.72	Polyamines reverse non-steroidal anti-inflammatory drug-induced toxicity in human colorectal cancer cells. ( Hughes, A; Smith, NI; Wallace, HM, 2003)
"We assayed the estrogen receptors and polyamine levels (putrescine, spermidine and spermine) in the neoplastic and "normal" surrounding tissue of patients with colorectal cancer."	3.68	Polyamines and estrogen-receptor concentrations in human colorectal carcinomas. ( Cavallini, A; Di Leo, A; Guerra, V; Lacatena, M; Lantone, G; Linsalata, M; Messa, C; Notarnicola, M; Russo, F, 1992)
"We assayed the estrogen and progesterone cytosolic receptors by using the enzyme immunoassay method, the epidermal growth factor (EGF) cell surface receptors by using 125I-labeled hormone, and the levels of polyamines (putrescine, spermine, and spermidine) by using a high-pressure liquid chromatography (HPLC) procedure in neoplastic and surrounding normal tissues of patients with colorectal cancer."	3.68	Sex steroid hormone receptors, epidermal growth factor receptor, and polyamines in human colorectal cancer. ( Cavallini, A; Di Leo, A; Linsalata, M; Messa, C; Russo, F, 1992)
"Chemoprevention is the long-term use of different chemical agents, both synthetic and natural, to prevent or delay the onset of disease."	2.50	Pharmacological and dietary agents for colorectal cancer chemoprevention: effects on polyamine metabolism (review). ( Linsalata, M; Orlando, A; Russo, F, 2014)
"Mean putrescine content was 1."	1.28	Colonic polyamine content and ornithine decarboxylase activity as markers for adenomas. ( Bartholomew, MJ; McGarrity, TJ; Pegg, AE; Peiffer, LP, 1990)
"Spermidine content was also significantly increased in the distal colon of EtOH-treated animals compared to baseline values."	1.27	The effects of chronic ethanol administration on polyamine content during dimethylhydrazine-induced colorectal carcinogenesis in the rat. ( Colony, PC; McGarrity, TJ; Pegg, AE; Peiffer, LP, 1988)

Research

Studies (16)

Authors

Clinical Trials (1)

Trial Overview

Trial Outcomes

Adverse Events With a Grade of 3 and Above

Timeframe	Studies, this research(%)	All Research%
pre-1990	1 (6.25)	18.7374
1990's	6 (37.50)	18.2507
2000's	3 (18.75)	29.6817
2010's	5 (31.25)	24.3611
2020's	1 (6.25)	2.80

Authors	Studies
Zhang, T	1
Hu, L	1
Tang, JF	1
Xu, H	1
Tian, K	1
Wu, MN	1
Huang, SY	1
Du, YM	1
Zhou, P	1
Lu, RJ	1
He, S	1
Xu, JM	1
Si, JJ	1
Li, J	1
Chen, DL	1
Ran, JH	1
Linsalata, M	3
Orlando, A	1
Russo, F	3
Pan, P	1
Skaer, CW	1
Wang, HT	1
Stirdivant, SM	1
Young, MR	1
Oshima, K	1
Stoner, GD	1
Lechner, JF	1
Huang, YW	1
Wang, LS	1
Rossi, G	1
Cerquetella, M	1
Pengo, G	1
Mari, S	1
Balint, E	1
Bassotti, G	1
Manolescu, N	1
Zhang, X	1
Chen, Y	1
Hao, L	1
Hou, A	1
Chen, X	1
Li, Y	1
Wang, R	1
Luo, P	1
Ruan, Z	1
Ou, J	1
Shi, C	1
Miao, H	1
Liang, H	1
Thompson, PA	1
Wertheim, BC	1
Zell, JA	1
Chen, WP	1
McLaren, CE	1
LaFleur, BJ	1
Meyskens, FL	2
Gerner, EW	2
Weiss, TS	1
Bernhardt, G	1
Buschauer, A	1
Thasler, WE	1
Dolgner, D	1
Zirngibl, H	1
Jauch, KW	1
Hughes, A	1
Smith, NI	1
Wallace, HM	2
Gervais, A	1
Levêque, J	1
Bouet-Toussaint, F	1
Burtin, F	1
Lesimple, T	1
Sulpice, L	1
Patard, JJ	1
Genetet, N	1
Catros-Quemener, V	1
Mackarel, AJ	1
Emerson, SS	1
Pelot, D	1
Meshkinpour, H	1
Shassetz, LR	1
Einspahr, J	1
Alberts, DS	1
Giardiello, FM	1
Hamilton, SR	1
Hylind, LM	1
Yang, VW	1
Tamez, P	1
Casero, RA	1
Messa, C	2
Cavallini, A	2
Notarnicola, M	1
Guerra, V	1
Lantone, G	1
Lacatena, M	1
Di Leo, A	2
McGarrity, TJ	2
Peiffer, LP	2
Bartholomew, MJ	1
Pegg, AE	2
Colony, PC	1

Trial	Phase	Enrollment	Study Type	Start Date	Status
A Phase III Randomized, Double-Blind, Placebo-Controlled Clinical Trial of the Combination of DFMO and Sulindac to Decrease the Rate of Recurrence of Adenomatous Polyps in the Colon[NCT00118365]	Phase 3	375 participants (Actual)	Interventional	1998-07-31	Completed
[information is prepared from clinicaltrials.gov, extracted Sep-2024]

"Participants reported at least 1 adverse event with a grade of 3 and above, regardless if the event is defined as serious per protocol or other.~Per protocol, not all grade 3 events are considered as serious events." (NCT00118365)
Timeframe: Up to 36 months

Baseline Putrescine by ODC Genotype

Intervention	participants (Number)
Arm I (Eflornithine and Sulindac)	46
Arm II (Placebo)	37

ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete. (NCT00118365)
Timeframe: Baseline

Baseline Spermidine by ODC Genotype

Intervention	nmol/mg protein (Median)
ODC1 AA/GA	0.47
ODC1 GG	0.56

Baseline Spermine by ODC Genotype

Intervention	nmol/mg protein (Median)
ODC1 AA/GA	1.99
ODC1 GG	2.17

Biomarker in Adenoma - Ki-67

Intervention	nmol/mg protein (Median)
ODC1 AA/GA	6.82
ODC1 GG	7.29

Estimated mean percent of cells staining postivie for the Ki-67 based on the GEE approach with adjustment for covariates (NCT00118365)
Timeframe: At the end of the study

Biomarker in Adenoma - p53

Intervention	percentage of cells that are positive (Mean)
Arm I (Eflornithine and Sulindac)	59.5
Arm II (Placebo)	63.9

"Estimated mean percent of cells staining postivie for p53 based on GEE approach with adjument for covariates.~Tumor protein p53, also known as p53, cellular tumor antigen p53, phosphoprotein p53, or tumor suppressor p53, is a protein that in humans is encoded by the TP53 gene." (NCT00118365)
Timeframe: At the end of the study

Number of Participants Have Adenoma Recurrence in Each ODC1 Genotytpe by Treatment Group

Intervention	percentage of cells that are positive (Mean)
Arm I (Eflornithine and Sulindac)	75.6
Arm II (Placebo)	70.3

At the End of the Study - Putrescine Response by ODC Genotype

Intervention	participants (Number)
DFMO + Sulindac - GG	7
DFMO + Sulindac - AA/GA	9
Placebo - GG	22
Placebo - AA/GA	18

"Putrescine responder was defined as (tissue putrescine value at baseline - tissue putrescine value at the end of the study)/(tissue putrescine value at baseline) ≥ the threshold. Putrescine non-responder was defined as (tissue putrescine value at baseline - tissue putrescine value at the end of the study)/(tissue putrescine value at baseline) < the threshold. The thresholds range from 0.25 to 0.45 with an increment of 0.5. The below data are shown for the threshold of 0.30.~ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete." (NCT00118365)
Timeframe: At the end of the study

At the End of the Study - Spermidine Response by ODC Genotype

Intervention	participants (Number)
	Responder	Non-Responder
DFMO + Sulindac - AA/GA	21	19
DFMO + Sulindac - GG	26	32
Placebo - AA/GA	12	37
Placebo - GG	12	31

"Spermidine responder was defined as (tissue spermidine value at baseline - tissue spermidine value at the end of the study)/(tissue spermidine value at baseline) ≥ the threshold. Spermidine non-responder was defined as (tissue spermidine value at baseline - tissue spermidine value at the end of the study)/(tissue spermidine value at baseline) < the threshold. The thresholds range from 0.25 to 0.45 with an increment of 0.5. The below data are shown for the threshold of 0.30.~ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete." (NCT00118365)
Timeframe: At the end of the study

At the End of the Study - Spermine Response by ODC Genotype

Intervention	participants (Number)
	Responder	Non-Responder
DFMO + Sulindac - AA/GA	12	28
DFMO + Sulindac - GG	25	32
Placebo - AA/GA	11	38
Placebo - GG	15	28

"Spermine responder was defined as (tissue spermine value at baseline - tissue spermine value at the end of the study)/(tissue spermine value at baseline) ≥ the threshold. Spermine non-responder was defined as (tissue spermine value at baseline - tissue spermine value at the end of the study)/(tissue spermine value at baseline) < the threshold. The thresholds range from 0.25 to 0.45 with an increment of 0.5. The below data are shown for the threshold of 0.30.~ODC genotype is the genotype of single nucleotide polymorphisms (SNP) in the ornithine decarboxylase (ODC) promoter The analysis cohort is based on the participants whose data are available and complete." (NCT00118365)
Timeframe: At the end of the study

Biomarker in Adenoma: Apoptosis

Intervention	participants (Number)
	Responder	Non-Responder
DFMO + Sulindac - AA/GA	7	33
DFMO + Sulindac - GG	7	51
Placebo - AA/GA	10	39
Placebo - GG	18	25

Apoptosis expression was assessed using cytoplasmic staining. The definitions for the category level for the Apoptosis are: 1. focal (less than 10% cells that are positively stained); 2. less than 50% cells are positively stained; 3. more than 50% cells are positively stained. (NCT00118365)
Timeframe: At the end of the study

Biomarker in Adenoma: Bcl-2

Intervention	adenoma (Number)
	A pattern equal to normal mucosa	1.focal (<10%)	2.cyto less than 50%	3.cyto more than 50%
Arm I (Eflornithine and Sulindac)	2	7	1	2
Arm II (Placebo)	4	20	23	13

bcl-2 is the anti-apoptotic protein BCL2 (NCT00118365)
Timeframe: At the end of the study, up to 3 years

Biomarker in Adenoma: CEA

Intervention	Adenoma (Number)
	A pattern equal to normal mucosa	1.<10% of the cells in the adenoma showed staining	2.10-50% cells showed staining	3.>50% cells showed staining	Insufficient tissue
Arm I (Eflornithine and Sulindac)	4	4	3	1	0
Arm II (Placebo)	17	25	14	8	2

carcino-embryonic antigen (CEA) is adenocarcinoma tissue marker that is expressed during adenoma formation. (NCT00118365)
Timeframe: At the end of the study

Biomarker in Adenoma: Sialyl-TN (B72.3)

Intervention	Adenoma (Number)
	A pattern equal to normal mucosa	1.<50% of cells showed staining	2.50-90% of cells showed staining	3.>90% of cells showed staining	Insufficient tissue
Arm I (Eflornithine and Sulindac)	1	5	6	0	0
Arm II (Placebo)	5	15	35	9	2

sialyl-Tn (B72.3) is adenocarcinoma tissue marker that is expressed during adenoma formation. (NCT00118365)
Timeframe: At the end of the study

Detection of Any Adenoma at the End of the Study

Intervention	Adenoma (Number)
	a pattern equal to normal mucosa	1.<10% of the cells in the adenoma showed staining	2.10-50% cells showed staining	3.>50% cells showed staining	Insufficient tissue
Arm I (Eflornithine and Sulindac)	3	7	2	0	0
Arm II (Placebo)	11	32	17	5	1

Detection of any adenoma at the end of the study. This analysis is based on the participants who had the end-of-study colonscopy procedure done. (NCT00118365)
Timeframe: Up to 36 months

Detection of Any Adenoma at the End of the Study Stratified by Baseline Prostaglandin E2 (PGE2) and Treatment

Intervention	participants (Number)
	Yes	No
Arm I (Eflornithine and Sulindac)	17	121
Arm II (Placebo)	53	76

This analysis is based on the participants who had the end-of-study colonscopy procedure done and their baseline PGE2 values are available. The low PGE2 is defined as the values that are below the median PGE2 value in the analysis cohort. The high PGE2 is defined as the values that are above the median PGE2 value in the analysis cohort. (NCT00118365)
Timeframe: Up to 36 months

Detection of Any Adenoma at the End of the Study Stratified by Baseline Putrescine and Treatment

Intervention	participants (Number)
	Yes	No
Eflornithine and Sulindac + High PGE2 at Baseline	3	41
Eflornithine and Sulindac + Low PGE2 at Baseline	12	41
Placebo + High PGE2 at Baseline	21	32
Placebo + Low PGE2 at Baseline	19	23

The low is defined as the values that are below the median putrescine level in the analysis cohort. The high is defined as the values that are above the median putrescine level in the analysis cohort. (NCT00118365)
Timeframe: Up 36 months

Detection of Any Adenoma at the End of the Study Stratified by Baseline Spermidine-to-spermine Ratio and Treatment

Intervention	participants (Number)
	Yes	No
Eflornithine and Sulindac + High Putrescine at Baseline	10	56
Eflornithine and Sulindac + Low Putrescine at Baseline	7	63
Placebo + High Putrescine at Baseline	31	36
Placebo + Low Putrescine at Baseline	24	38

"The low is defined as the ratios that are below the median spermidine-to-spermine ratio in the analysis cohort. The high is defined as the ratios that are above the median spermidine-to-spermine ratio in the analysis cohort.~In the finalized datasaet, the total number of adnoma detected in the placebo group is 55. The descrepancy in the total number of adnoma detected in placebo group between Outcome Measure 1 and this oucome is due to the revolution of the datatset.~The analysis cohort is based on the participants whose data are available and complete." (NCT00118365)
Timeframe: Up 36 months

Detection of Any Adenoma at the End of the Study Stratified by Prostaglandin E2 (PGE2) Response and Treatment

Intervention	participants (Number)
	Yes	No
Eflornithine and Sulindac + High Spd:Spm at Baseline	12	60
Eflornithine and Sulindac + Low Spd:Spm at Baseline	5	59
Placebo + High Spd:Spm at Baseline	24	37
Placebo + Low Spd:Spm at Baseline	31	37

PGE2 Responder = PGE2 values at 36-month are decreased by >=30% in PGE2 values from baseline PGE2 nonresponder = PGE2 values at 36-month are increased, or decreased by < 30% from baseline The analysis cohort is based on the participants whose data are available and complete. (NCT00118365)
Timeframe: Up to 36 months

Detection of Any Adenoma at the End of the Study Stratified by Putrescine Response and Treatment

Intervention	participants (Number)
	Yes	No
Eflornithine and Sulindac + PGE2 Nonresponders	8	27
Eflornithine and Sulindac + PGE2 Responders	1	10
Placebo + PGE2 Nonresponders	15	17
Placebo + PGE2 Responders	4	13

Putrescine responder = Putrescine values at 36-month are decreased by >=30% from baseline Putrescine nonresponder = Putrescine values at 36-month are increased, or decreased by < 30% from baseline The analysis cohort is based on the participants whose data are available and complete. (NCT00118365)
Timeframe: Up to 36 months

Detection of Any Adenoma at the End of the Study Stratified by Spermidine-to-spermine Ratio Response and Treatment

Intervention	participants (Number)
	Yes	No
Eflornithine and Sulindac + Putrescine Nonresponders	7	53
Eflornithine and Sulindac + Putrescine Responders	9	52
Placebo + Putrescine Nonresponders	28	44
Placebo + Putrescine Responders	22	24

Spermidine-to-spermine ratio responder = ratios at 36-month are decreased by >=30% from baseline Spermidine-to-spermine ratio nonresponder = ratios at 36-month are increased, or decreased by < 30% from baseline The analysis cohort is based on the participants whose data are available and complete. (NCT00118365)
Timeframe: Up to 36 months

Article	Year
Levels of rectal mucosal polyamines and prostaglandin E2 predict ability of DFMO and sulindac to prevent colorectal adenoma. Gastroenterology, 2010, Volume: 139, Issue:3 Topics: Adenoma; Aged; Anticarcinogenic Agents; Biomarkers, Pharmacological; Biopsy; Colonoscopy; Colorectal	2010
Dose de-escalation chemoprevention trial of alpha-difluoromethylornithine in patients with colon polyps. Journal of the National Cancer Institute, 1994, Aug-03, Volume: 86, Issue:15 Topics: Administration, Oral; Adult; Aged; Biogenic Polyamines; Colonic Polyps; Colorectal Neoplasms; Drug A	1994

Article	Year
Metformin Inhibits the Urea Cycle and Reduces Putrescine Generation in Colorectal Cancer Cell Lines. Molecules (Basel, Switzerland), 2021, Apr-01, Volume: 26, Issue:7 Topics: Animals; Biomarkers; Cell Cycle Checkpoints; Cell Line, Tumor; Cell Proliferation; Colorectal Neopla	2021
Black raspberries suppress colonic adenoma development in ApcMin/+ mice: relation to metabolite profiles. Carcinogenesis, 2015, Volume: 36, Issue:10 Topics: Adenoma; Adenomatous Polyposis Coli Protein; alpha-Linolenic Acid; Animals; Colorectal Neoplasms; Di	2015
Immunohistochemical expression of ornithine decarboxylase, diamine oxidase, putrescine, and spermine in normal canine enterocolic mucosa, in chronic colitis, and in colorectal cancer. BioMed research international, 2015, Volume: 2015 Topics: Amine Oxidase (Copper-Containing); Animals; Chronic Disease; Colitis; Colorectal Neoplasms; Dogs; In	2015
Macrophages induce resistance to 5-fluorouracil chemotherapy in colorectal cancer through the release of putrescine. Cancer letters, 2016, 10-28, Volume: 381, Issue:2 Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Caspase 3; Colorectal Neoplasms; Drug Resistanc	2016
Polyamine levels of human colorectal adenocarcinomas are correlated with tumor stage and grade. International journal of colorectal disease, 2002, Volume: 17, Issue:6 Topics: Acetyltransferases; Adenocarcinoma; Aged; Biomarkers, Tumor; Chromatography, Liquid; Colorectal Neop	2002
Polyamines reverse non-steroidal anti-inflammatory drug-induced toxicity in human colorectal cancer cells. The Biochemical journal, 2003, Sep-01, Volume: 374, Issue:Pt 2 Topics: Anti-Inflammatory Agents, Non-Steroidal; Apoptosis; Cell Division; Cell Membrane; Cell Survival; Col	2003
Dendritic cells are defective in breast cancer patients: a potential role for polyamine in this immunodeficiency. Breast cancer research : BCR, 2005, Volume: 7, Issue:3 Topics: Aged; Antineoplastic Agents; Breast Neoplasms; Carcinoma, Ductal, Breast; Carcinoma, Intraductal, No	2005
An investigation of the mechanism of polyamine efflux from human colorectal carcinoma cells. Biochemical Society transactions, 1994, Volume: 22, Issue:4 Topics: Cell Line; Colorectal Neoplasms; Humans; Kinetics; Polyamines; Putrescine; Spermidine; Spermine; Tum	1994
Ornithine decarboxylase and polyamines in familial adenomatous polyposis. Cancer research, 1997, Jan-15, Volume: 57, Issue:2 Topics: Adenomatous Polyposis Coli; Adolescent; Adult; Biomarkers, Tumor; Child; Colorectal Neoplasms; Femal	1997
Polyamines and estrogen-receptor concentrations in human colorectal carcinomas. The Italian journal of gastroenterology, 1992, Volume: 24, Issue:1 Topics: Adenocarcinoma; Adult; Aged; Carcinoembryonic Antigen; Colorectal Neoplasms; Female; Humans; Intesti	1992
Sex steroid hormone receptors, epidermal growth factor receptor, and polyamines in human colorectal cancer. Diseases of the colon and rectum, 1992, Volume: 35, Issue:4 Topics: Adult; Aged; Colon; Colorectal Neoplasms; ErbB Receptors; Female; Humans; Intestinal Mucosa; Male; M	1992
Colonic polyamine content and ornithine decarboxylase activity as markers for adenomas. Cancer, 1990, Oct-01, Volume: 66, Issue:7 Topics: Aged; Biogenic Polyamines; Biomarkers, Tumor; Colonic Polyps; Colorectal Neoplasms; Female; Humans;	1990
The effects of chronic ethanol administration on polyamine content during dimethylhydrazine-induced colorectal carcinogenesis in the rat. Carcinogenesis, 1988, Volume: 9, Issue:11 Topics: Animals; Colon; Colorectal Neoplasms; Dimethylhydrazines; Ethanol; Polyamines; Putrescine; Rats; Rat	1988

putrescine and Colorectal Cancer