Differential enhancement of melphalan cytotoxicity in tumor and normal tissue by fluosol‐DA^® and oxygen breathing

Abstract

The addition of Fluosol-DA carbogen breathing to melphalan treatment of the FSa-IIC fibrosarcoma was assessed by tumor growth delay and cell survival assays. Melphalan (10 mg/kg) administered intraperitoneally (i.p.) was preceded by Fluosol-DA (0.3 ml) administered intravenously (i.v.) and followed by 1 hr of carbogen breathing; this resulted in a tumor growth delay of 9.5 +/- 1.4 days or an approximately 3-fold increase compared to melphalan alone. Melphalan produced about 1.7 logs of cell killing; neither carbogen breathing nor Fluosol-DA pretreatment altered the cell killing observed. There was a 10-fold increase in tumor-cell killing when Fluosol-DA was administered immediately prior to melphalan administration followed by carbogen breathing for 1 hr. Density gradient separation identified a population of denser FSa-IIC cells which showed increased sensitivity to melphalan after Fluosol-DA administration. There was no additional toxicity to bone marrow as measured by CFU-GM with the combination of melphalan/Fluosol-DA/O2 compared to melphalan alone.

Antitumor Agents, 130. Novel 4β-Arylamino Derivatives of 3',4'-Didemethoxy-3',4'-dioxo-4-deoxypodophyllotoxin as Potent Inhibitors of Human DNA Topoisomerase II

“…int.) 498 (15), 369 (16), 277 (8), 247(10), 185 (83), 119 (16), 93(100). Yield 94%; crystals from toluene; mp215-218°; ir (KBr) 3360, 2900, 1760, 1645, 1615, 1555 cm"1; *H nmr (CDC13) 7.67 (dj = 8.5 Hz, 1H, H-5"), 6.73 (s, 1H, H-5), 6.53 (s, 1H, H-8), 6.52 (d, 7= 1.5 Hz, 1H, H-6'), 6.05 (m, 2H, H-2", -6"), 6.01 and 6.00(ABq,7= 1.2 Hz, 2H, OCH20), 5.28 (dj = 1.5 Hz, 1H, H-2'), 4.71 (dd,7 = 6.5, 5.0 Hz, 1H, H-4), 4.58 (tj= 8.0 Hz, 1H, H-ll), 4.29 (d J= 5.5 Hz, 1H, H-l), 4.23 (dj= 6.5 Hz, 1H, exchangeable, NH), 4.05 (ddj = 9.6, 8.0 Hz, 1H, H-ll), 3.91 (s, 3H, C02Me), 3.85 (s, 3H, 5'-OMe), 3.26 (dd,7= 14.0, 5.5 Hz, 1H, H-2), 3.01 (m, 1H, H-3).…”

“…Dehydrogenase inhibitors or substrates and some free-radical scavengers were found to be capable of inhibiting l-induced DNA damage and cytotoxicity (15). Compound 1 was also found to be 30-fold more toxic to normally oxygenated EMT6 mouse mammary cells than to hypoxic cells (16). The in vivo antitumor activity of 1 against FS all C fibrosarcoma and Lewis lung carcinoma was increased considerably by oxygenation of the tumor tissue prior to administration of the drug (16,17).…”

“…Compound 1 was also found to be 30-fold more toxic to normally oxygenated EMT6 mouse mammary cells than to hypoxic cells (16). The in vivo antitumor activity of 1 against FS all C fibrosarcoma and Lewis lung carcinoma was increased considerably by oxygenation of the tumor tissue prior to administration of the drug (16,17). Because of the involvement of free radicals in these processes, a radical-mediated mechanism of action was suggested to account for the DNA damage by 1.…”

“…3',4'-Didemethoxy-3',4'-dioxoAß-(3''-hydroxyA"-methoxycarbonylanilino)-4-deoxypodophyllotoxin[ 16].- …”

Aryltetralin Lignans: Chemistry, Pharmacology and Biotransformations

“…Compound 7a was also found to be 30fold more toxic to normally oxygenated EMT6 mouse mammary cells than to hypoxic cells [32]. The in vivo antitumour activity of 7a against FS all C fibrosarcoma and Lewis lung carcinoma was increased considerably by oxygenation to the tumour tissue prior administration of the drug [32,33]. Because of the involvement of free radicals in these processes, a radical-mediated mechanism of action was suggested to account for the DNA damage by 7a.…”