STRATEGIES FOR SELECTIVE CANCER PHOTOCHEMOTHERAPY: ANTIBODY‐TARGETED and SELECTIVE CARCINOMA CELL PHOTOLYSIS*

Photochemistry and Photobiology - Tập 46 Số 1 - Trang 83-96 - 1987
Allan R. Oseroff1,2, Gulshan Ara2, D. Ohuoha1,2, June R. Aprille3, Jerry C. Bommer4, Martin L. Yarmush5, J Foley6,7, Louis Cincotta6,7
1Department of Dermatology, New England Medical Center, Boston, MA 02111, USA.
2Wellman Laboratory, Department of Dermatology, Massachusetts General Hospital, Boston, MA 02114, USA
3Department of Biology, Tufts University, Medford, MA, USA
4Porphyrin Products, Inc., Logan, UT 84321, USA
5Department of Chemical Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139 USA
62142, USA
7Rowland Institute for Science, Cambridge, MA

Tóm tắt

Abstract A principle objective in chemotherapy is the development of modalities capable of selectively destroying malignant cells while sparing normal tissues. One new approach to selective photochemo‐therapy, antibody‐targeted photolysis (ATPL) uses photosensitizers (PS) coupled to monoclonal antibodies (MAbs) which bind to eel) surface antigens on malignant cells. Selective destruction of human T leukemia cells (HBP‐ALL) was accomplished by coupling the efficient PS chlorin e6 to an anti‐T cell MAb using dextran carriers. Conjugates with chlorin : MAb ratios of 30 : 1 retained > 85% MAb binding activity, and had a quantum yield for singlet oxygen production of 0.7 ±0.1, the same as that of free chlorin e6. Cell killing was dependent on the doses of both MAb‐PS and 630‐670 nm light, and occurred only in target cell populations which bound the MAb. On the order of 1010 singlet oxygen molecules were necessary to kill a cell.A second approach to specific photochemotherapy, selective carcinoma cell photolysis (SCCP), relies on preferential accumulation of certain cationic PS by carcinoma cell mitochondria. We have evaluated several classes of cationic dyes, and in the case of N,N′‐bis‐(2‐ethyl‐1,3‐dioxolane)‐krypto‐cyanine (EDKC) and some of its analogs, have demonstrated highly selective killing of human squamous cell, bladder and colon carcinoma cells in vitro. In isolated mitochondria, EDKC uptake and fluorescence depended on membrane potential, and the dye specifically photosensitized damage to Complex I in the electron transport chain. N,N′‐bis‐(2‐ethyl‐1,3‐dioxolane)‐kryptocyanine and some of its analogs accumulated within subcutaneous xenografts of human tumors in nude mice with tumor : skin ratios > 8. Photoirradiation caused significant inhibition of tumor growth, without cutaneous phototoxicity.

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Photochemistry and Photobiology

Tập 46 Số 1

83-96

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