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Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis.
Cancer Chemother Pharmacol. 2004 Nov; 54(5):421-31.CC

Abstract

PURPOSE

To test the anticancer properties of a nonhydrolyzable ether-linked acetic acid analogue of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (alpha-TEA), and a derivative of camptothecin, 9-nitrocamptothecin (9-NC)singly and in combination against mouse mammary tumor cells (line 66 clone 4 stably transfected with green fluorescent protein; 66cl-4-GFP) cultured in vitro or transplanted subcutaneously into the inguinal region of female BALB/c mice to form established tumors.

METHODS

Following in vitro treatment of 66cl-4-GFP cells with alpha-TEA and suboptimal concentrations of 9-NC, singly or in combination, apoptosis was measured by morphological evaluation of nuclei stained with 4',6-diamidino-2-phenylindole (DAPI), and DNA synthesis arrest was measured by tritiated thymidine uptake. For in vivo analyses alpha-TEA and 9-NC, both water-insoluble compounds, were formulated into liposomes using dil-auroylphosphatidylcholine and administered by aerosol to deliver doses calculated to be 36 and 0.4 microg/mouse per day, respectively, (singly or each separately for combined treatments) 7 days per week.

RESULTS

Treatment of 66cl-4-GFP cells in culture for 3 days with a combination of alpha-TEA (10 microg/ml; singly produces 38% apoptosis), and suboptimal concentrations of 9-NC(15.6, 31.3, 62.5, or 125 ng/ml; singly produce 2-7% apoptosis), produced 47%, 58%, 64%, and 69% apoptosis. Likewise, combinations of alpha-TEA 9-NC inhibited DNA synthesis more than either agent administered singly. A significant reduction (P< 0.001)in growth of subcutaneous transplanted tumors was observed with liposome-formulated and aerosolized delivery of alpha-TEA + 9-NC to BALB/c mice. The incidence of macroscopic lung metastasis was 83% in control vs 8 % in alpha-TEA-, 9-NC-, or combination-treated mice. Fluorescence microscopic examination of lungs and axillary and brachial lymph nodes showed a statistically significant decrease in metastasis observed in alpha-TEA-,9-NC-, and combination- vs control-treated animals. Analyses of primary tumor tissue for proliferation and apoptosis showed treatment groups to have lower Ki-67 and higher terminal deoxynucleotidyl transferase-mediated nick end labeling, respectively. Treatments showed no measurable effects on two angiogenesis parameters,namely intratumoral blood volume as assessed by hemoglobin content and intratumoral blood vessel density as assessed with CD31 staining.

CONCLUSIONS

Combination treatments enhanced antiproliferative and proapoptotic activities in cell culture, and when formulated in liposomes and delivered via aerosolization to treat an aggressive and metastatic syngeneic murine mammary tumor, the combination treatment showed a significant reduction in tumor volume in comparison to either treatment alone. Mechanistically, it appears that neither enhanced apoptosis, reduced cell proliferation,nor reduced blood vessel density can fully account for the enhanced effects of the combination treatment.

Authors+Show Affiliations

Cancer Prevention Fellowship Program, National Cancer Institute, NIH, DHHS, Bethesda, MD 20892, USA.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo 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

15197487

Citation

Lawson, Karla A., et al. "Novel Vitamin E Analogue and 9-nitro-camptothecin Administered as Liposome Aerosols Decrease Syngeneic Mouse Mammary Tumor Burden and Inhibit Metastasis." Cancer Chemotherapy and Pharmacology, vol. 54, no. 5, 2004, pp. 421-31.
Lawson KA, Anderson K, Snyder RM, et al. Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis. Cancer Chemother Pharmacol. 2004;54(5):421-31.
Lawson, K. A., Anderson, K., Snyder, R. M., Simmons-Menchaca, M., Atkinson, J., Sun, L. Z., Bandyopadhyay, A., Knight, V., Gilbert, B. E., Sanders, B. G., & Kline, K. (2004). Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis. Cancer Chemotherapy and Pharmacology, 54(5), 421-31.
Lawson KA, et al. Novel Vitamin E Analogue and 9-nitro-camptothecin Administered as Liposome Aerosols Decrease Syngeneic Mouse Mammary Tumor Burden and Inhibit Metastasis. Cancer Chemother Pharmacol. 2004;54(5):421-31. PubMed PMID: 15197487.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Novel vitamin E analogue and 9-nitro-camptothecin administered as liposome aerosols decrease syngeneic mouse mammary tumor burden and inhibit metastasis. AU - Lawson,Karla A, AU - Anderson,Kristen, AU - Snyder,Rachel M, AU - Simmons-Menchaca,Marla, AU - Atkinson,Jeffrey, AU - Sun,Lu-Zhe, AU - Bandyopadhyay,Abhik, AU - Knight,Vernon, AU - Gilbert,Brian E, AU - Sanders,Bob G, AU - Kline,Kimberly, PY - 2004/6/16/pubmed PY - 2004/12/16/medline PY - 2004/6/16/entrez SP - 421 EP - 31 JF - Cancer chemotherapy and pharmacology JO - Cancer Chemother Pharmacol VL - 54 IS - 5 N2 - PURPOSE: To test the anticancer properties of a nonhydrolyzable ether-linked acetic acid analogue of vitamin E, 2,5,7,8-tetramethyl-2R-(4R,8R, 12-trimethyltridecyl)chroman-6-yloxyacetic acid (alpha-TEA), and a derivative of camptothecin, 9-nitrocamptothecin (9-NC)singly and in combination against mouse mammary tumor cells (line 66 clone 4 stably transfected with green fluorescent protein; 66cl-4-GFP) cultured in vitro or transplanted subcutaneously into the inguinal region of female BALB/c mice to form established tumors. METHODS: Following in vitro treatment of 66cl-4-GFP cells with alpha-TEA and suboptimal concentrations of 9-NC, singly or in combination, apoptosis was measured by morphological evaluation of nuclei stained with 4',6-diamidino-2-phenylindole (DAPI), and DNA synthesis arrest was measured by tritiated thymidine uptake. For in vivo analyses alpha-TEA and 9-NC, both water-insoluble compounds, were formulated into liposomes using dil-auroylphosphatidylcholine and administered by aerosol to deliver doses calculated to be 36 and 0.4 microg/mouse per day, respectively, (singly or each separately for combined treatments) 7 days per week. RESULTS: Treatment of 66cl-4-GFP cells in culture for 3 days with a combination of alpha-TEA (10 microg/ml; singly produces 38% apoptosis), and suboptimal concentrations of 9-NC(15.6, 31.3, 62.5, or 125 ng/ml; singly produce 2-7% apoptosis), produced 47%, 58%, 64%, and 69% apoptosis. Likewise, combinations of alpha-TEA 9-NC inhibited DNA synthesis more than either agent administered singly. A significant reduction (P< 0.001)in growth of subcutaneous transplanted tumors was observed with liposome-formulated and aerosolized delivery of alpha-TEA + 9-NC to BALB/c mice. The incidence of macroscopic lung metastasis was 83% in control vs 8 % in alpha-TEA-, 9-NC-, or combination-treated mice. Fluorescence microscopic examination of lungs and axillary and brachial lymph nodes showed a statistically significant decrease in metastasis observed in alpha-TEA-,9-NC-, and combination- vs control-treated animals. Analyses of primary tumor tissue for proliferation and apoptosis showed treatment groups to have lower Ki-67 and higher terminal deoxynucleotidyl transferase-mediated nick end labeling, respectively. Treatments showed no measurable effects on two angiogenesis parameters,namely intratumoral blood volume as assessed by hemoglobin content and intratumoral blood vessel density as assessed with CD31 staining. CONCLUSIONS: Combination treatments enhanced antiproliferative and proapoptotic activities in cell culture, and when formulated in liposomes and delivered via aerosolization to treat an aggressive and metastatic syngeneic murine mammary tumor, the combination treatment showed a significant reduction in tumor volume in comparison to either treatment alone. Mechanistically, it appears that neither enhanced apoptosis, reduced cell proliferation,nor reduced blood vessel density can fully account for the enhanced effects of the combination treatment. SN - 0344-5704 UR - https://www.unboundmedicine.com/medline/citation/15197487/Novel_vitamin_E_analogue_and_9_nitro_camptothecin_administered_as_liposome_aerosols_decrease_syngeneic_mouse_mammary_tumor_burden_and_inhibit_metastasis_ L2 - https://dx.doi.org/10.1007/s00280-004-0817-y DB - PRIME DP - Unbound Medicine ER -