Chromophore-modified bis-naphthalimides: synthesis and antitumor activity of bis-dibenz[de,h]isoquinoline-1,3-diones.

The bis-dibenz[de,h]isoquinoline-1,3-diones are a new series of antitumor agents that consist of two chromophores bridged by an alkylamino linker. In the present study we have explored the effect produced by the presence of two dibenz[de,h]isoquinoline-1,3-dione moieties with different polyamine chains on cellular cytotoxicity. Bis-dibenz[de,h]isoquinoline-1,3-diones with the bridge (CH2)2-NH-(CH2)n-NH-(CH2)2, where n = 2-5, showed optimum cytotoxicity with IC50's around 10 nM. Compound 16, which has the (CH2)2-NH-(CH2)3-NH-(CH2)2 bridge, altered DNA mobility and topoisomerase I and II activity at approximately 5 microM. When tested in vivo, compound 16 increased the median survival time of mice implanted with M5076 with an optimum %T/C of 154% and produced cures in 50% of mice implanted with Lox melanoma.

Bis-naphthalimides 3: synthesis and antitumor activity of N,N'-bis[2-(1,8-naphthalimido)-ethyl] alkanediamines.

The bis-naphthalimides are a new class of antitumor agent. Previously, we have described initial synthetic series which established that two naphthalimide chromophores joined by polyamine linkers can produce agents with antitumor activity. We now extend these studies to describe the synthesis of a N,N'-bis[1,8-naphthalimido)-ethyl]alkanediamine series and examine the alkyl linker and chromophore substitution requirements for optimal antitumor activity. As a result, a bis-naphthal-imidoethyl derivative with no chromophore substitution and a NH-(CH2)3-NH bridge was identified. This agent (LU 79553) had both potent cellular cytotoxicity (IC50 = 0.014 microM) and was curative against MX-1 tumors grown in athymic mice. It has now been selected for clinical development.

Preclinical evaluation of LU 79553: a novel bis-naphthalimide with potent antitumor activity.

LU 79553 is a novel bis-naphthalimide which is highly cytotoxic in vitro with EC50 (concentration required for 50% inhibition of growth) ranging from 2 x 10(-7) to 5 x 10(-10) M. A number of studies were conducted to examine its antitumor activity in human xenograft models. In addition, we wanted to explore the possible schedule dependency of LU 79553 cytotoxicity in these xenograft models. Complete regression of MX-1 (mammary carcinoma) xenografts was observed when LU 79553 was administered i.v. daily for 5 doses at 20 mg/kg (2 cycles starting on Days 6 and 20) or every 3 days for 2 doses at 55 mg/kg (2 cycles starting on Days 6 and 13) or every 7 days for 4 doses. Complete regression was also seen in the MX-1 model when tumors were staged at 1-2 g prior to the initiation of treatment. Regressions (complete or partial) were observed in the LX-1 (lung), CX-1 (colon), DLD (colon), and LOX (melanoma) xenograft models. A significant increase in the median survival time of OVCAR-3- (ovarian carcinoma) bearing mice was noted in LU 79553-treated animals (treated/control = 195%). The excellent activity of this compound in such a wide variety of tumor types suggests LU 79553 merits further investigation in clinical trials.

Effects of cytochalasin B in culture and in vivo on murine Madison 109 lung carcinoma and on B16 melanoma.

Cytochalasin B (CB), at 100 or at 10 mg/kg single dose s.c. in carboxymethyl-cellulose (2%)/Tween-20 (1%) 24 h after s.c. challenge of B6D2F1 mice with trocar implants of B16F10 tumor s.c., delayed the appearance of measurable tumor nodules by 157 and 93%, respectively, and extended host survival by 65 and 26%. Tumor growth was also delayed when CB treatment was given 1 day after the appearance of palpable tumor nodules. By in vivo bioassay, in vitro cloning, and dye exclusion measurements, solid tumor nodules treated in vivo with CB at either 100 or 10 mg/kg showed the same viability and tumorigenicity as did vehicle-treated nodules 4 and 6 days after drug treatment, at which time growth inhibition was still apparent. This indicates that growth inhibition by CB is not dependent on a gross cytotoxic effect. CD2F1 mice challenged s.c. with Madison 109 lung carcinoma cells and treated with CB s.c. at 100 or 150 mg/kg 24 h later showed a 66% delay in the median day of tumor nodule appearance. When administered under these conditions or at the time of nodule appearance. CB markedly inhibited the rate of tumor growth, prevented tumor invasion at day 23, extended life span by 23%, and significantly inhibited spontaneous lung metastases measured 28 days after tumor challenge. Maximum tolerated doses of CB administered i.p., s.c., or i.v. in suspension or in solution are defined. These results delineate the conditions under which CB can be tested for in vivo biological activities and establish that this microfilament-active natural product in a single-agent protocol inhibits local tumor growth and extends survival in B16F10 melanoma and Madison 109 lung carcinoma, and, in the latter model, inhibits invasion and spontaneous lung metastases by mechanisms that do not appear to depend on cytotoxicity. This work on formulation, tolerated doses in vivo, and localized peritumoral effects of CB now permits evaluation of systemic antitumor effects of cytochalasin B as a single agent. It also permits chemotherapy studies using CB as a potential amplifier of the activity of other antitumor agents in vivo.