Critical appraisals of approaches for predictive designs in anticancer drugs.

The present review provides a critical appraisal of the most important areas in cancer drug research and, ultimately, in clinical oncology and therapy, with emphasis on the elucidation of possible predictive designs for the development of new anticancer drugs. These assessments encompass the well-established anticancer drugs and congeners which have been employed over the years in clinical therapy, and the more recent exploratory agents still requiring further rigorous scrutiny in the clinical environment. These areas mainly include the bioreversible redox carriers, the boron neutron capture compounds, some new mitosis-interactive agents, cell cycle modifiers, biological-response mpdifiers, oncogene inhibitors, drug-antibody conjugates, cancer cell suppression and destruction agents, antiangiogenesis and antimetastasis agents, apoptosis-promoting agents, and gene therapy and vaccines.

In the search for new anticancer drugs. 27. Synthesis and comparison of anticancer activity in vivo of amino acids, carbohydrates, and carbohydrate-amino acid conjugates containing the [N'-(2-chloroethyl)-N'-nitrosoamino]carbonyl group.

The [N'-(2-chloroethyl)-N'-nitrosoamino]carbonyl [(2-chloroethyl)nitrosocarbamoyl, CNC] moiety containing compounds CNC-glycinamide 2d, CNC-amino acid derivatives 7a-d, and carbohydrate-CNC-amino acid conjugates 13, 18, 22, 23, 27, and 28 were synthesized and evaluated in vivo for their anticancer activities against the murine lymphocytic leukemia P388 using the National Cancer Institute (NCI) protocol. The most active compound was 2d with a 520% increase in life span (%ILS) and 6/6 survivors after 60 days. The CNC-amino acid analogs 7a-d possessed high to moderate activities with maximum %ILS values of 270, 174, 141 and 132, respectively. Among the carbohydrate-CNC-amino acid derivatives the alpha-methyl glycoside derivatives 22 and 23 were most active with maximum %ILS values of 277 and 137, respectively, followed by the hemiacetal carbohydrate analogs 13 and 18 with %ILS values of 93 and 149, respectively, and the tetra-O-acetyl derivatives 27 and 28 with %ILS of 110 and 111, respectively. Compounds 7b, 18, 23 and 28 were then tested in vivo against the murine lymphoid leukemia L1210 using the NCI protocol. In this case, the hemiacetal type carbohydrate-CNC-amino analog 18 had the highest activity with a maximum %ILS value of 477 and 4/6 survivors on day 60, followed by 7b (275% ILS), 23 (152% ILS) and 28 (106% ILS). The lipophilicities of all CNC compounds were determined by the partition coefficient using the UV method. A correlation of %ILS values with log P values indicated, in general, an increase in cytotoxicity with a decrease in hydrophilicity for the carbohydrate-CNC-amino acid conjugates 13, 18, 22, 23 and the clinical drugs streptozotocin (1e), chlorozotocin (1f), and cymerin (1g).

In the search for new anticancer drugs. XXV: Role of N-nitrosated amadori compounds derived from glucose-amino acid conjugates in cancer promotion or inhibition.

Earlier investigators found that some N-nitrosated Amadori compounds, derived from glucose and amino acid condensation reactions, exhibit mutagenic properties and theorized that these potentially carcinogenic compounds might be formed in the human digestive system. To further investigate these compounds, N-nitrosated Amadori compounds [i.e., N-(1-deoxy-D-fructos-1-yl)-L-N-nitroso-glycine (5a), -threonine (5b), -methionine (5c), -valine (5d), -phenylalanine (5e), and -tryptophan (5f)] were synthesized by modifications of known methods. Acute toxicity tests of 5a, 5b, 5c, 5d, 5e, and 5f in male Swiss mice produced the following lowest lethal limits of toxicity: 2000, 2000, 4000, 3000, 2000, and 6000 mg/kg, respectively, whereas the highest tolerated doses were 1750, 1500, 3000, 1500, and 5000 mg/kg, respectively. The 50% lethal dose (intraperitoneally) for 5b in mice was approximately 1777 mg/kg. This value is at least three times higher than that for the over-the-counter drug ibuprofen (i.e., 495 mg/kg, intraperitoneally, in mice). Compounds 5b, 5c, 5d, and 5f were evaluated in vitro by the National Cancer Institute primary antitumor screen consisting of 60 cell lines. None of the four compounds caused a significant inhibition of cell growth, even at the maximum dosage of 10(-4) M. Compounds 5a-f were tested in vivo against the lymphocytic leukemia P388, and 5b and 5f were tested against the lymphoid leukemia L1210 in CDF1 male mice following the National Cancer Institute protocol. There were no significant differences in results between the control and drug-treated mice.(ABSTRACT TRUNCATED AT 250 WORDS)