ENHANCEMENT OF ANTITUMOR DRUG CYTOTOXICITY via LASER PHOTOACTIVATION

Abstract

We investigate the efficacy of daunomycin, some imino- and amino-substituted daunomycin analogues and the disubstituted aminoanthracenedione, mitoxantrone, in photosensitizing short-term cell kill upon irradiation in the long wavelength visible range, during incubation of Fisher rat thyroid cells with the drugs. While all compounds exhibit similar cytocidal effects on our cell line, in the absence of irradiation, administering 86 J/cm2 at wavelengths either coincident or close to drug absorption peaks causes greater enhancement in cell mortality for the 4-demethoxydaunomycin analogues than either the parent drug or its 5-imino-derivative. A lower enhancement is observed with mitoxantrone. In particular, C50 doses (i.e. concentrations that would kill 50% cells) as low as approximately 10(-9) M are found for both 6- and 11-amino 4-demethoxydaunomycin, compared with the values obtained in the absence of light, which are 2.59 x 10(-4) and 0.43 x 10(-4) M, respectively. Our previous studies of the photophysical and photochemical properties of the excited states of these drugs, and ESR and spin trapping studies of photosensitized generation of singlet oxygen, which were extended in this work to include mitoxantrone, indicate that the cytocidal effects proceed via type I rather than type II mechanisms.

Improved photochemotherapy of malignant cells with daunomycin and the KTP laser

“…The current studies corroborate and extend previous in vitro experiments that demonstrate that anthracyclines have dual properties as photodynamic agents and as cytostatic anticancer drugs [1,8,[16][17][18][19]. For example, a recent in vitro study with Adriamycin using explanted human squamous-cell carcinoma showed that exposure to the argon laser at 514 nm led to over 50% increased cytotoxicity at drug levels equal to or above 5 g/ml compared to chemotherapy alone in the dark [19].…”

“…Andreoni et al first reported laser-amplified anthracycline toxicity in vitro in normal rodent cells [16]. Saxton et al [17] found that carcinoma cells incubated with daunomycin can be killed by nonthermal 514.5-nm argon laser illumination at tenfold reduced drug levels compared to drug alone in the dark.…”

“…Spinlabel experiments also have demonstrated that slow light activation of Dn induces chemical bonding to many different cell membrane proteins [5]. Absorption of photons by aromatic organic compounds increases kinetic energy levels and may excite orbital electrons, leading to chemical reactions as well as inducing light emission as fluorescence, or may transfer energy directly to oxygen molecules, forming singlet oxygen and/or free radical species [16].…”

Laser Photo Chemotherapy: An Alternative Treatment for Cancer

“…The author also compared different anti-cancer agents combined with LITT ablation for inoperable esophageal cancer and reported that cisplatin (CDDP) was more effective than anthracyclines or cyclophosphamide when combined with Nd:YAG laser. However, other studies done in children with retinoblastoma found that Adriamycin derivatives were more cytotoxic in tumors after laser photo-thermal activation (Andreoni et al, 1991;Gallie et al, 1996;Lippert et al, 2004;Lueder and Goyal, 1996;Murphree et al, 1996). From a historical perspective, initial work on chemotherapy and lasers was reported in clinical models investigating combined palliative therapy for inoperable esophageal cancers.…”

“…In PDT, the absorption of photons by organic compounds can excite orbital electrons and increase kinetic energy levels leading to chemical reactions, but also may include light emission as fluorescence or transfer energy directly to oxygen molecules forming singlet and free radical species (Carmichael et al, 1983;Paiva et al, 1996). Anthracyline derivatives, such as adriamycin and daunomycin, are the most common anticancer agents that interact with light to elicit fluorescence, membrane photo labeling, laser activation and killing of tumor cells (Andreoni et al, 1991;Nahabedian et al, 1988;Saxton et al, 1996). Studies with these anticancer agents include reports of excited states of these drugs and further generation of radical oxygen species which appear to be wavelength dependent, from 313 to 498nm .…”