Activity and distribution studies of etoposide and mitozolomide in vivo and in vitro against human choriocarcinoma cell lines.

The in vivo antitumor activity of etoposide and mitozolomide was assessed in nude mice bearing a xenograft (CC3) of human gestational choriocarcinoma. Both agents demonstrated, at best, marginal activity observed as a delay in tumour growth. This lack of sensitivity suggests that the CC3 xenograft is not a good model for selection of agents for clinical evaluation in gestational choriocarcinoma. Plasma and tissue concentrations of etoposide and mitozolomide were measured in nude mice. Drug concentrations found in tumour tissue were 60% and 30% of plasma levels for mitozolomide and etoposide respectively. Etoposide and mitozolomide activity was also evaluated in vitro with another choriocarcinoma cell line (JAR). Maximum cell-kill was achieved after exposure to etoposide 0.05-1 microgram/ml for 3-24 h. In vitro response to etoposide demonstrates the importance of exposure time in determining cytotoxicity. In contrast, mitozolomide at concentrations from 1-100 micrograms/ml did not have a marked effect against JAR after exposure for 3-24 h.

In vivo studies with the novel anticancer agent mitozolomide (NSC 353451) on Lewis lung carcinoma.

Mitozolomide is one of the most effective drugs against Lewis lung carcinoma in the mouse. Two IP doses of 40 mg/kg (days 6 and 15 after IM transplantation of 3LL) or four doses of 20 mg/kg given at various intervals (starting from day 6) increased survival time by 100%. A single IP dose of 80 mg/kg was toxic, and 10 mg/kg was ineffective even when this dose was given on eight occasions. The pharmacokinetics of mitozolomide was investigated in 3LL-bearing mice by HPLC assay. Peak drug levels were achieved in tumor 15 min after IP treatment, after which they declined according to first-order kinetics, with a half-life of 80-100 min (the same as in plasma). No dose-dependent kinetics was observed. Flow cytometry studies showed an accumulation of 3LL cells in G2M 24 h after drug treatment. This cell cycle perturbation was reversed 96 h after the inactive dose of 10 mg/kg, but not after the effective dose of 40 mg/kg.

Spiromustine: a new agent entering clinical trials.

Spiromustine is a new alkylating agent, of interest since it was rationally designed as a lipophilic compound capable of penetrating the CNS. This lipophilicity may also enhance alkylating activity against tumors other than brain tumors. Preclinical screening has shown activity against a variety of tumors, including an intracranially implanted ependymoblastoma. Alkylating activity has been demonstrated in an intracerebral glioma in the rat. Spiromustine is a cell cycle non-specific agent. Animal pharmacology studies have shown a biphasic plasma decay curve, with hepatic metabolism and excretion, an enterohepatic circulation of metabolites, and approximately 50% renal excretion of unchanged drug. Toxicology studies in mice, rats and dogs showed that dose-related myelosuppression, and neurotoxicity predominated; other organ toxicities were mild. Spiromustine is currently entering Phase I clinical trials on a variety of schedules.

Potential anticancer agents. XVII. New developments in the benzoic acid nitrogen mustards area.

In order to obtain aromatic nitrogen mustards with improved therapeutic index against experimental neoplasms, greater than 75 new compounds were synthetized and studied. Their structure-activity relationship analysis led to the following conclusions: (a) the carboxylic group (especially when located in the meta position with respect to the nitrogen mustard group) exerts a favorable effect on the biologic properties of such compounds, probably by improving their transport characteristics; (b) a linear relationship was found between the chemical reactivity (expressed as alkylation rate, log k66) and toxicity (LD50) of 31 investigated compounds; and (c) the ortho effects also seem to be of importance in this area for a more accurate control of the nitrogen mustard activity. Other criteria (ie, log P, nucleophilicity of the target centers) involved in the rational design of aromatic nitrogen mustards are discussed. The design of new derivatives was oriented toward compounds which (a) were able to couple with selected proteins (ie, antibodies) leaving the cytotoxic moiety intact, and (b) were obtained by coupling of the 3-N,N-bis(2-chloroethyl)amino-4-methyl-benzoyl moiety with selected carriers (steroids, chromanones, etc) by way of an esteric bond.

Drug latentiation in cancer chemotherapy.

Latent antitumour agents require spontaneous or enzyme-catalysed activation to cytotoxic species in vivo. Activation may occur principally in normal tissues or in the target tumour. Agents of this type are discussed and mechanisms of drug action and selectivity are described, with reference to appropriate examples. The comparatively poor therapeutic activity of many agents designed for selective activation in tumours is attributed to the often unfavourable distribution of activating enzymes between normal and neoplastic tissues. Factors to be considered in the design of new enzyme-activated agents are discussed and possible artefacts involved in the assay of tumour enzymes are described. Some novel approaches to the design of latent antitumour agents are also discussed.