Effects of fludarabine and gemcitabine on human acute myeloid leukemia cell line HL 60: Direct comparison of cytotoxicity and cellular Ara-C uptake enhancement

Santini, Valeria; D’Ippolito, Gianluca; Bernabei, Pietro Antonio; Zoccolante, A; Ermini, Angela; Rossi-Ferrini, P

doi:10.1016/0145-2126(95)00106-9

Cited by 17 publications

(8 citation statements)

References 13 publications

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“…Somewhat analogous to the concept of non-chemo-therapeutic resistant cancer cell types, the cytotoxic anti-neoplatic potency of gemcibatine-(C 4 - amide )-[anti-HER2/ neu ] and gemcitabine-(C 5 methylcarbamate )-[anti-HER2/ neu ] could also have alternatively been measured against an entirely different neoplastic cell type such as pancreatic carcinoma, [95] small-cell lung carcinoma, [96] neuroblastoma, [97] or leukemia/lymphoid [60,98] populations due to their relatively higher gemcitabine sensitivity. Similarly, human promyelocytic leukemia, [40,60] T-4 lymphoblastoid clones, [60] glioblastoma, [40,60] cervical epitheliod carcinoma, [60] colon adenocarci-noma, [60] pancreatic adenocarcinoma, [60] pulmonary adenocarcinoma, [60] oral squamous cell carcinoma, [60] and prostatic carcinoma [21] have all been found to be sensitive to gemcitabine and gemcitabine-(oxyether phopholipid) covalently bonded chemotherapeutics.…”

Section: Discussionmentioning

confidence: 99%

Synthesis of Gemcitabine-(C4-amide)-[anti-HER2/neu] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

Coyne¹,

Jones²,

Bear³

2012

JCT

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Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated intracellularly where it competitively inhibits cytidine incorporation into DNA strands. Another mechanism-of-action of gemcitabine (diphosphorylated form) involves irreversible inhibition of the enzyme ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic gemcitabine promote decreases in neoplastic cell proliferation and apoptosis which is frequently found to be effective for the treatment of several leukemias and a wide spectrum of carcinomas. A brief plasma half-life in part due to rapid deamination and chemotherapeutic-resistance restricts the utility of gemcit-abine in clinical oncology. Selective “targeted” delivery of gemcitabine represents a potential molecular strategy for simultaneously prolonging its plasma half-life and minimizing innocient tissues and organ systems exposure to chemotherapy. The molecular design and an organic chemistry based synthesis reaction is described that initially generates a UV-photoactivated gemcitabine intermediate. In a subsequent phase of the synthesis method the UV-photoactivated gemcitabine intermediate is covalently bonded to a monoclonal immunoglobulin yielding an end-product in the form of gemcitabine-(C4-amide)-[anti-HER2/neu]. Analysis by SDS-PAGE/chemiluminescent auto-radiography did not detect evidence of gemcitabine-(C4-amide)-[anti-HER2/neu] polymerization or degradative fragmentation while cell-ELISA demonstrated retained binding-avidity for HER2/neu trophic membrane receptor complexes highly over-expressed by chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Compared to chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3), the covalent immunochemotherapeutic, gemcitabine-(C4-amide)-[anti-HER2/neu] is anticipated to exert greater levels of cytotoxic anti-neoplastic potency against other neoplastic cell types like pancreatic carcinoma, small-cell lung carcinoma, neuroblastoma, glioblastoma, oral squamous cell carcinoma, cervical epitheliod carcinoma, or leukemia/lymphoid neoplastic cell types based on their reported sensitivity to gemcitabine and gemcitabine covalent conjugates.

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Section: Discussionmentioning

confidence: 99%

Synthesis of Gemcitabine-(C4-amide)-[anti-HER2/neu] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

Coyne¹,

Jones²,

Bear³

2012

JCT

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“…Preliminary results for the combination of dFdC and cisplatin also suggest possible therapeutic synergism in non-small-cell lung cancer (18). Furthermore, numerous investigators have reported promising results of dFdC used in combination with udarabine (Fara-A) on human AML cell line HL-60 and on freshly isolated CLL cells in vitro (26,27).…”

Section: Discussionmentioning

confidence: 99%

Influence of gemcitabine (2′,2′‐difluoro‐deoxycytidine) and 2‐chlorodeoxyadenosine on growth of normal and leukemic cellsin vitro

Lech‐Marańda

Korycka

Robak

2000

European J of Haematology

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The aim of the study was to investigate the influence of gemcitabine (2',2'-difluorodeoxycytidine, dFdC) used alone and in combination with 2-chlorodeoxyadenosine (2-CdA) on the colony growth of normal granulocyte-macrophage progenitor cells (CFU-GM) from 15 hematologically healthy donors as well as on CFU-GM from 15 chronic myelogenous leukemia (CML) patients in semisolid cultures in vitro. dFdC and 2-CdA were used either separately or in the following combinations of concentrations: (1) 0.25 nM of dFdC and 2.5 nM of 2-CdA; (2) 0.5 nM of dFdC and 5 nM of 2-CdA; (3) 1 nM of dFdC and 10 nM of 2-CdA; (4) 2 nM of dFdC and 20 nM of 2-CdA. We observed that both dFdC and 2-CdA used separately inhibited the growth of colonies formed by normal and CML CFU-GM cells in a dose-dependent manner. Moreover, the combined therapy with dFdC and 2-CdA caused statistically significant inhibition of the colony growth in both normal and CML CFU-GM cultures. In addition, the inhibition of CML CFU-GM colony formation was greater and statistically significant in the case of the combined therapy using higher concentrations of these drugs as compared with inhibition of the growth of normal CFU-GM colonies. These observations were the basis for the evaluation of the interaction type between dFdC and 2-CdA. We have shown that dFdC used in a combination with 2-CdA acts in an additive way on normal and CML CFU-GM cells.

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“…Similarly, the cytotoxic anti-neoplatic potency of gemcibatine-(C 4 - amide )-[anti-HER2/ neu ] could also have alternatively been measured against an entirely diferent neoplastic cell type such as pancreatic carcinoma [52] small-cell lung carcinoma [53] neuroblastoma, [54] or leukemia/lymphoid [55,56] due to their relatively higher gemcitabine sensitivity. In addition, human promyelocytic leukemia [24,55], T-4 lymphoblastoid clones [55], glioblastoma [24,55], cervical epitheliod carcinoma [55], colon adenocarcinoma [55], pancreatic adenocarcinoma [55], pulmonary adenocarcinoma [55], oral squamous cell carcinoma [55], and prostatic carcinoma [57] have been found to be sensitive to gemcitabine and covalent gemcitabine-(oxyether phopholipid) preparations.…”

Section: Discussionmentioning

confidence: 99%

Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicty in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma

2018

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Introduction Gemcitabine is a pyrimidine nucleoside analog that becomes triphosphorylated and competitively inhibits cytidine incorporation into DNA strands. Diphosphorylated gemcitabine irreversibly inhibits ribonucleotide reductase thereby preventing deoxyribonucleotide synthesis. Functioning as a potent chemotherapeutic, gemcitabine decreases neoplastic cell proliferation and induces apoptosis which accounts for its effectiveness in the clinical treatment of several leukemia and carcinoma cell types. A brief plasma half-life due to rapid deamination, chemotherapeutic-resistance and sequelae restrict gemcitabine utility in clinical oncology. Selective “targeted” gemcitabine delivery represents a molecular strategy for prolonging its plasma half-life and minimizing innocent tissue/organ exposure. Methods A previously described organic chemistry scheme was applied to synthesize a UV-photoactivated gemcitabine intermediate for production of gemcitabine-(C4-amide)-[anti-HER2/neu]. Immunodetection analysis (Western-blot) was applied to detect the presence of any degradative fragmentation or polymerization. Detection of retained binding-avidity of gemcitabine-(C4-amide)-[anti-HER2/neu] was determined by cell-ELISA using populations of chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3) that highly over-express the HER2/neu trophic membrane receptor. Cytotoxic anti-neoplastic potency of gemcitabine-(C4-amide)-[anti-HER2/neu] and the benzimidazole tubulin/microtubule inhibitors, albendazole, flubendazole and mebendazole was established against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Related investigations evaluated the potential for gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with mebendazole to evoke increased levels of cytotoxic anti-neoplatic potency compared to gemcitabine-(C4-amide)-[anti-HER2/neu]. Results Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic and each benzimidazole (n=3) exerted cytotoxic anti-neoplastic potency against chemotherapeutic-resistant mammary adenocarcinoma (SKBr-3). Covalent gemcitabine-(C4-amide)-[anti-HER2/neu] immunochemotherapeutic or gemcitabine in dual combination with mebendazole created increased levels of cytotoxic anti-neoplastic potency that were greater than attained with gemcitabine-(C4-amide)-[anti-HER2/neu] or gemcitabine alone. Conclusion Gemcitabine-(C4-amide)-[anti-HER2/neu] in dual combination with benzimidazoles can produce enhanced levels of cytotoxic anti-neoplastic activity and potentially provide a basis for treatment regimens with a wider margin-of-safety. Such benefits would be possible through the collective properties of; [i] selective “targeted” gemcitabine delivery; [ii] relatively lower toxicity of benzimidazoles compared to many if not most conventional chemotherapeutics; [iii] reduced total dosage requirements faciliated by additive or synergistic anti-cancer properties; and [iv] differences in sequelae for gemcitabine-(C4-amide)-[anti-HER2/neu] compared to benzimidazole tubulin/microtu...

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Effects of fludarabine and gemcitabine on human acute myeloid leukemia cell line HL 60: Direct comparison of cytotoxicity and cellular Ara-C uptake enhancement

Cited by 17 publications

References 13 publications

Synthesis of Gemcitabine-(C<sub>4</sub>-<i>amide</i>)-[anti-HER2/<i>neu</i>] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

Synthesis of Gemcitabine-(C<sub>4</sub>-<i>amide</i>)-[anti-HER2/<i>neu</i>] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

Influence of gemcitabine (2′,2′‐difluoro‐deoxycytidine) and 2‐chlorodeoxyadenosine on growth of normal and leukemic cellsin vitro

Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicty in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma

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Effects of fludarabine and gemcitabine on human acute myeloid leukemia cell line HL 60: Direct comparison of cytotoxicity and cellular Ara-C uptake enhancement

Cited by 17 publications

References 13 publications

Synthesis of Gemcitabine-(C&lt;sub&gt;4&lt;/sub&gt;-&lt;i&gt;amide&lt;/i&gt;)-[anti-HER2/&lt;i&gt;neu&lt;/i&gt;] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

Synthesis of Gemcitabine-(C&lt;sub&gt;4&lt;/sub&gt;-&lt;i&gt;amide&lt;/i&gt;)-[anti-HER2/&lt;i&gt;neu&lt;/i&gt;] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

Influence of gemcitabine (2′,2′‐difluoro‐deoxycytidine) and 2‐chlorodeoxyadenosine on growth of normal and leukemic cellsin vitro

Gemcitabine-(C4-amide)-[anti-HER2/neu] Anti-Neoplastic Cytotoxicty in Dual Combination with Mebendazole against Chemotherapeutic-Resistant Mammary Adenocarcinoma

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Synthesis of Gemcitabine-(C<sub>4</sub>-<i>amide</i>)-[anti-HER2/<i>neu</i>] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3

Synthesis of Gemcitabine-(C<sub>4</sub>-<i>amide</i>)-[anti-HER2/<i>neu</i>] Utilizing a UV-Photoactivated Gemcitabine Intermediate: Cytotoxic Anti-Neoplastic Activity against Chemotherapeutic-Resistant Mammary Adenocarcinoma SKBr-3