The role of gemcitabine in the treatment of other tumours

Carmichael, James

doi:10.1038/bjc.1998.750

Cited by 109 publications

(64 citation statements)

References 24 publications

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“…Moreover GSG could also be applied to other types of cancer that have been confirmed to express the GnRH-R and are sensitive to gemcitabine treatment such as breast, ovarian, bladder and pancreatic cancers. 24,26 In conclusion, the lead compound presented in this manuscript, GSG, shows a potent anticancer effect that appears to be associated with a dual mode of action: 1) improved efficacy due to reduced metabolic inactivation of gemcitabine and 2) targeted delivery to cancer cells over-expressing the GnRH-R. We believe that the work presented herein could lead to valuable insights associated with gemcitabine treatment and possibly improve the therapeutic options of androgen independent CaP patients.…”

Section: Discussionmentioning

confidence: 78%

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Καράμπελας

Argyros

Sayyad³

et al. 2014

Bioconjugate Chem.

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Gemcitabine, a drug with established efficacy against a number of solid tumors, has therapeutic limitations due to its rapid metabolic inactivation. The aim of this study was the development of an innovative strategy to produce a metabolically stable analogue of gemcitabine that could also be selectively delivered to prostate cancer (CaP) cells based on cell surface expression of the Gonadotropin Releasing HormoneReceptor (GnRH-R). The synthesis and evaluation of conjugated molecules, consisting of gemcitabine linked to a GnRH agonist, is presented along with results in androgen-independent prostate cancer models. NMR and ligand binding assays were employed to verify conservation of microenvironments responsible for binding of novel GnRH-gemcitabine conjugates to the GnRH-R. In vitro cytotoxicity, cellular uptake and metabolite formation of the conjugates were examined in CaP cell lines. Selected conjugates were efficacious in the in vitro assays with one of them, namely GSG, displaying high antiproliferative activity in CaP cell lines along with significant metabolic and pharmacokinetic advantages in comparison to gemcitabine. Finally, treatment of GnRH-R positive xenografted mice with GSG, showed a significant advantage in tumor growth inhibition when compared to gemcitabine. 3 IntroductionDespite advancements in methods for early cancer detection and improved insights into the molecular mechanisms and treatment options, advanced prostate cancer (CaP) remains a major health problem for the aging man. 1,2 Hormonal therapy is usually the first line of defense for CaP treatment by using drugs that lead to chemical castration, suppression of testosterone and dihydrotestosterone (DHT) biosynthesis. 3,4 The hormonal ablation approach has been achieved successfully using agonist (through desensitization) or antagonist analogue drugs, of the native Gonadotropin Releasing Hormone (GnRH). These drugs exert their effects primarily on the pituitary gland through the GnRH-R by lowering gonadotropins and downstream gonadal sex steroids. Nevertheless, in many cases after treatment, following initial tumor regression, CaP progresses to an androgen-independent state with poor prognosis, which presents a major challenge for the physician and the patient. 3,[5][6][7][8][9][10] Research on the GnRH-R has shown that its expression is not confined solely to the pituitary but that is also present in several other tissues such as prostate, breast 11-13 and the GnRH-R level of expression along with cell context is critical for cell responses to either agonist or antagonist drugs of the receptor. 14 It is also well established that GnRH-R gene expression is upregulated in patients with androgenindependent CaP, making the GnRH-R an attractive target for the design of novel and specific therapeutics. 15 A modern approach to improve conventional chemotherapy is by direct targeting of chemotherapeutic agents to cancer cells in order to enhance the tumoricidal effect and reduce peripheral toxicity of a specific drug. Linking chemo...

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Section: Discussionmentioning

confidence: 78%

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

Καράμπελας

Argyros

Sayyad³

et al. 2014

Bioconjugate Chem.

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“…Resistance can be either inherent or acquired. Inherent resistance is a quality of several tumor types, which is reflected in low response rates in clinical trials (6). Acquired resistance can develop by selection of cells from a heterogeneous tumor cell population during repetitive treatment with a drug.…”

Section: Introductionmentioning

confidence: 99%

In vivo Induction of Resistance to Gemcitabine Results in Increased Expression of Ribonucleotide Reductase Subunit M1 as the Major Determinant

Bergman¹,

Eijk

Haperen³

et al. 2005

Cancer Research

170

128

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Gemcitabine is a deoxycytidine (dCyd) analogue with activity against several solid cancers. Gemcitabine is activated by dCyd kinase (dCK) and interferes, as its triphosphate dFdCTP, with tumor growth through incorporation into DNA. Alternatively, the metabolite gemcitabine diphosphate (dFdCDP) can interfere with DNA synthesis and thus tumor growth through inhibition of ribonucleotide reductase. Gemcitabine can be inactivated by the enzyme dCyd deaminase (dCDA). In most in vitro models, resistance to gemcitabine was associated with a decreased dCK activity. In all these models, resistance was established using continuous exposure to gemcitabine with increasing concentrations; however, these in vitro models have limited clinical relevance. To develop in vivo resistance to gemcitabine, we treated mice bearing a moderately sensitive tumor Colon 26-A (T/C = 0.25) with a clinically relevant schedule (120 mg/kg every 3 days). By repeated transplant of the most resistant tumor and continuation of gemcitabine treatment for >1 year, the completely resistant tumor Colon 26-G (T/C = 0.96) was created. Initial studies focused on resistance mechanisms known from in vitro studies. In Colon 26-G, dCK activity was 1.7-fold decreased; dCDA and DNA polymerase were not changed; and Colon 26-G accumulated 1.5-fold less dFdCTP, 6 hours after a gemcitabine injection, than the parental tumor. Based on in vitro studies, these relative minor changes were considered insufficient to explain the completely resistant phenotype. Therefore, an expression microarray was done with Colon 26-A versus Colon 26-G. Using independently grown nonresistant and resistant tumors, a striking increase in expression of the RRM1 subunit gene was found in Colon 26-G. The expression of RRM1 mRNA was 25-fold increased in the resistant tumor, as measured by real-time PCR, which was confirmed by Western blotting. In contrast, RRM2 mRNA was 2-fold decreased. However, ribonucleotide reductase enzyme activity was only moderately increased in Colon 26-G. In conclusion, this is the first model with in vivo induced resistance to gemcitabine. In contrast to most in vitro studies, dCK activity was not the most important determinant of gemcitabine resistance. Expression microarray identified RRM1 as the gene with the highest increase in expression in the Colon 26-G, which might clarify its complete gemcitabine-resistant phenotype. This study is the first in vivo evidence for a key role for RRM1 in acquired gemcitabine resistance. (Cancer Res 2005; 65(20): 9510-6)

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“…GEM is a deoxycytidine analog that has significant singleagent activity against a number of malignancies, including pancreatic cancer (10,11). GEM is transported into cells via the human equilibrative nucleoside transporter-1 (hENT1) (12) and must be phosphorylated by deoxycytidine kinase (dCK) to be activated.…”

Section: Introductionmentioning

confidence: 99%

Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil

et al. 2011

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Abstract. Gemcitabine (GEM) is the standard treatment for advanced/metastatic pancreatic cancer. However, there is a substantial subset of patients in whom the efficacy of GEM, when used as a single agent, is inadequate. Recently, the 5-fluorouracil (5-FU) prodrugs capecitabine and S-1 have been used as an alternative, either alone or in combination with GEM. The aim of the present study was to investigate the expression pattern of genes that render pancreatic cancer cells sensitive to GEM and 5-FU, and to identify markers for individualized chemotherapy, even in patients who have developed resistance. We investigated the correlation between the expression of genes associated with the metabolism of GEM and 5-FU, and sensitivity to these drugs in 15 human pancreatic cancer cell lines. We also established GEM-and 5-FU-resistant pancreatic cancer cell lines to investigate changes in the expression levels of these genes and the effects of one drug on cells resistant to the other. We found no correlation between pancreatic cancer cell sensitivity to either GEM-or 5-FU. GEM-resistant cells did not become resistant to 5-FU and vice versa. High expression of RRM1 (P=0.048) and TS x DPD (P= 0.035) correlated significantly with sensitivity to GEM and 5-FU, respectively. 5-FU-resistant cells expressed significantly higher levels of TP than parental cells (P<0.05). In conclusion, pancreatic cancer cells showed no crossresistance to GEM and 5-FU. Quantitative analyses of RRM1, TP, DPD and TS mRNA levels in pancreatic cancer cells may be useful for predicting their sensitivity to GEM and 5-FU.

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The role of gemcitabine in the treatment of other tumours

Cited by 109 publications

References 24 publications

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

GnRH-Gemcitabine Conjugates for the Treatment of Androgen-Independent Prostate Cancer: Pharmacokinetic Enhancements Combined with Targeted Drug Delivery

In vivo Induction of Resistance to Gemcitabine Results in Increased Expression of Ribonucleotide Reductase Subunit M1 as the Major Determinant

Predicting the chemosensitivity of pancreatic cancer cells by quantifying the expression levels of genes associated with the metabolism of gemcitabine and 5-fluorouracil

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