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Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethylene glycol) conjugates in sensitive and multidrug-resistant human ovarian carcinoma cells.
Cancer Chemother Pharmacol. 2002 Aug; 50(2):143-50.CC

Abstract

BACKGROUND

Camptothecin (CPT) is an anticancer agent that kills cells by converting DNA topoisomerase I into a DNA-damaging agent. Although CPT and its derivatives are now being used to treat tumors in a variety of clinical protocols, the low water solubility of the drug and its unique pharmacodynamics and reactivity in vivo limit its delivery to cancer cells. To increase the anticancer efficacy of CPT a special drug delivery system is needed.

PURPOSE

To synthesize a novel camptothecin-poly(ethylene glycol) conjugate (CPT-PEG) which includes biotin as a moiety to enhance nonspecific and/or targeted uptake via the sodium-dependent multivitamin transporter (SMVT) and to evaluate its anticancer activity and apoptosis induction.

METHODS

CPT-PEG and CPT-PEG-biotin conjugates were synthesized and studied in vitro in A2780 sensitive and A2780/AD multidrug-resistant human ovarian carcinoma cells. Cytotoxicity, apoptosis induction, expression of genes encoding BCL-2 and apoptotic protease-activating factor 1 (APAF-1) proteins and caspases 3 and 9 as well as caspase activity were measured.RESULTS. We found that the conjugation of CPT with a simple linear PEG polymer led to a more than 12-fold enhancement of CPT toxicity in both sensitive and multidrug-resistant cells. Biotinylation of the PEG led to a further increase in CPT toxicity (5.2 times in sensitive and 2.1 times in multidrug-resistant cells) compared to the nonbiotinylated CPT-PEG conjugate. As a result, the cytotoxicity of the CPT-PEG-biotin conjugate increased more than 60 times in sensitive and almost 30 times in resistant cells, probably by enhancing nonspecific passive and/or SMVT-mediated uptake. In contrast, the same amounts of PEG and PEG-biotin conjugates without CPT did not induce cell death in either sensitive or resistant cells. Further analysis showed that the biotinylated CPT-PEG conjugate induced apoptosis more significantly than the same equivalent concentrations of free CPT or nonbiotinylated CPT-PEG. The enhancement of proapoptotic activity was achieved by the overexpression of genes encoding the APAF-1, and caspases 3 and 9, increasing caspase activity and simultaneously downregulating the BCL-2 gene.

CONCLUSIONS

The results obtained demonstrate that the binding of CPT to PEG/PEG-biotin polymers increases its cytotoxicity, ability to induce apoptosis by the activation of caspase-dependent cell death signaling pathway and simultaneous suppression of antiapoptotic cellular defense. This suggests that the targeting approach utilizing transporters such as SMVT may substantially improve the delivery of CPT and its anticancer activity by enhancing cellular permeability and possibly retention of CPT.

Authors+Show Affiliations

Center for Biomaterials, 610 Taylor Road, Piscataway, NJ 08854, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, P.H.S.

Language

eng

PubMed ID

12172980

Citation

Minko, Tamara, et al. "Enhancing the Anticancer Efficacy of Camptothecin Using Biotinylated Poly(ethylene Glycol) Conjugates in Sensitive and Multidrug-resistant Human Ovarian Carcinoma Cells." Cancer Chemotherapy and Pharmacology, vol. 50, no. 2, 2002, pp. 143-50.
Minko T, Paranjpe PV, Qiu B, et al. Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethylene glycol) conjugates in sensitive and multidrug-resistant human ovarian carcinoma cells. Cancer Chemother Pharmacol. 2002;50(2):143-50.
Minko, T., Paranjpe, P. V., Qiu, B., Lalloo, A., Won, R., Stein, S., & Sinko, P. J. (2002). Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethylene glycol) conjugates in sensitive and multidrug-resistant human ovarian carcinoma cells. Cancer Chemotherapy and Pharmacology, 50(2), 143-50.
Minko T, et al. Enhancing the Anticancer Efficacy of Camptothecin Using Biotinylated Poly(ethylene Glycol) Conjugates in Sensitive and Multidrug-resistant Human Ovarian Carcinoma Cells. Cancer Chemother Pharmacol. 2002;50(2):143-50. PubMed PMID: 12172980.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Enhancing the anticancer efficacy of camptothecin using biotinylated poly(ethylene glycol) conjugates in sensitive and multidrug-resistant human ovarian carcinoma cells. AU - Minko,Tamara, AU - Paranjpe,Pankaj V, AU - Qiu,Bo, AU - Lalloo,Anita, AU - Won,Roney, AU - Stein,Stanley, AU - Sinko,Patrick J, Y1 - 2002/06/11/ PY - 2001/10/15/received PY - 2002/03/14/accepted PY - 2002/8/13/pubmed PY - 2002/10/9/medline PY - 2002/8/13/entrez SP - 143 EP - 50 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother. Pharmacol. VL - 50 IS - 2 N2 - BACKGROUND: Camptothecin (CPT) is an anticancer agent that kills cells by converting DNA topoisomerase I into a DNA-damaging agent. Although CPT and its derivatives are now being used to treat tumors in a variety of clinical protocols, the low water solubility of the drug and its unique pharmacodynamics and reactivity in vivo limit its delivery to cancer cells. To increase the anticancer efficacy of CPT a special drug delivery system is needed. PURPOSE: To synthesize a novel camptothecin-poly(ethylene glycol) conjugate (CPT-PEG) which includes biotin as a moiety to enhance nonspecific and/or targeted uptake via the sodium-dependent multivitamin transporter (SMVT) and to evaluate its anticancer activity and apoptosis induction. METHODS: CPT-PEG and CPT-PEG-biotin conjugates were synthesized and studied in vitro in A2780 sensitive and A2780/AD multidrug-resistant human ovarian carcinoma cells. Cytotoxicity, apoptosis induction, expression of genes encoding BCL-2 and apoptotic protease-activating factor 1 (APAF-1) proteins and caspases 3 and 9 as well as caspase activity were measured.RESULTS. We found that the conjugation of CPT with a simple linear PEG polymer led to a more than 12-fold enhancement of CPT toxicity in both sensitive and multidrug-resistant cells. Biotinylation of the PEG led to a further increase in CPT toxicity (5.2 times in sensitive and 2.1 times in multidrug-resistant cells) compared to the nonbiotinylated CPT-PEG conjugate. As a result, the cytotoxicity of the CPT-PEG-biotin conjugate increased more than 60 times in sensitive and almost 30 times in resistant cells, probably by enhancing nonspecific passive and/or SMVT-mediated uptake. In contrast, the same amounts of PEG and PEG-biotin conjugates without CPT did not induce cell death in either sensitive or resistant cells. Further analysis showed that the biotinylated CPT-PEG conjugate induced apoptosis more significantly than the same equivalent concentrations of free CPT or nonbiotinylated CPT-PEG. The enhancement of proapoptotic activity was achieved by the overexpression of genes encoding the APAF-1, and caspases 3 and 9, increasing caspase activity and simultaneously downregulating the BCL-2 gene. CONCLUSIONS: The results obtained demonstrate that the binding of CPT to PEG/PEG-biotin polymers increases its cytotoxicity, ability to induce apoptosis by the activation of caspase-dependent cell death signaling pathway and simultaneous suppression of antiapoptotic cellular defense. This suggests that the targeting approach utilizing transporters such as SMVT may substantially improve the delivery of CPT and its anticancer activity by enhancing cellular permeability and possibly retention of CPT. SN - 0344-5704 UR - https://www.unboundmedicine.com/medline/citation/12172980/Enhancing_the_anticancer_efficacy_of_camptothecin_using_biotinylated_poly_ethylene_glycol__conjugates_in_sensitive_and_multidrug_resistant_human_ovarian_carcinoma_cells_ L2 - https://dx.doi.org/10.1007/s00280-002-0463-1 DB - PRIME DP - Unbound Medicine ER -