Allen Richard Kraska

CP-46,665-1: A novel lipoidal amine with antimetastatic and immunomodulatory properties

SummaryCP-46-665-1 [4-aminomethyl-1(2,3-(di-n-decyloxy)-n-propyl)-4-phenylpiperidine dihydrochloride] is a novel, low-molecular-weight, synthetic compound with antimetastatic activity in rodent models. In the B-16 melanoma/C57Bl/6 mouse system, in which the hind limb bearing a primary foot tumor is amputated 21 days after tumor implantation, intravenous infusion of CP-46,665-1 after surgery at doses ranging from 0.15–2.5 mg/kg increases the fraction of metastasis-free animals at 50 days to as high as 56% (significantly different from the 19% seen in surgery-only controls, P<0.001). In more preliminary experiments with a mammary adenocarcinoma (13762)/Fischer 344 rat system, there are suggestions that the combination of CP-46,665-1 administration and surgical removal of the primary tumor results in increased numbers of long-term survivors that are free of metastatic disease.The mechanisms underlying the antimetastatic activity of CP-46,665-1 are not fully evident, but certain lines of evidence suggest that the compound may act by affecting the reticuloendothelial system (RES). Peritoneal macrophages from animals dosed with CP-46,665-1 display elevated cytolytic activity against tumor target cells. Further, radiolabeled CP-46,665-1 and/or its metabolites preferentially accumulate in organs of the RES, and lymph nodes, spleens, and livers from animals dosed chronically with CP-46,665-1 contain scattered foci of histiocytic cells with foamy vacuoles containing material staining as complex lipid. CP-46,665-1 augments the vaccine potency of irradiated L-1210 leukemia cells, but does not induce interferon in rodents.CP-46,665-1 appeared to be well tolerated in rats and dogs when infused at doses of up to 25 mg/kg at 4-day intervals for 92 days. In addition to the changes in the lymphoreticular system described above, the principal findings in dogs that received high doses by injection were erythrocyte lysis accompanied by the expected serum chemistry and hematological correlates; microcytic anemia and injection site irritation were found in rats receiving high doses. Neither species displayed notable toxic reactions when chronically dosed at the 1 mg/kg level, a level well within the antimetastatic activity dose range. Cats and dogs with a variety of malignancies tolerated weekly doses of the agent as high as 5 mg/kg with minimal side-effects for periods up to 30 weeks. We believe that this combination of good chronic toleration and potent antimetastatic activity commend CP-46,665-1 well for more extensive study as an experimental drug for the treatment of cancer.

Chapter 14 Antineoplastic Agents

Publisher Summary This chapter summarizes the researches and discoveries of different antineoplastic agents regarding the treatment of cancer. Several naturally occurring compounds or their derivatives have received considerable attention in recent years because of their clinical potential. Some structural requirements for another class of naturally occurring antineoplastics, the quassinoids, have been studied, and it has been determined that the epoxymethano bridge and C-1 and C-12 hydroxyls are necessary for biological activity. Adriamycin has continued to be the dominant force in the expanding use of chemotherapeutic agents. Its wide spectrum of activity coupled with its dose-limiting cardiac toxicity continues to stimulate the search for structurally modified agents with improved biological profiles. The 14-diethoxyacetoxy derivative of daunorubicin also showed superior antitumor activity with a greater than two-fold increase in therapeutic index. High dose methotrexate (MTX) followed by folinic acid rescue has found application in a wide variety of tumors. Thymidine (TdR) has also recently been reported to be effective as a rescue agent for high dose MTX. Gallium nitrate, a heavy metal compound active in animal tumor systems and shown to be nonmyelosuppressive, has provided responses in initial clinical studies in Hodgkins disease lymphoma, ovarian cancer, and osteogenic sarcoma. Aspirin and Indomethacin, inhibitors of PG biosynthesis, have been reported to inhibit the growth of a 3-methylcholanthrene (Meth A)-induced fibrosarcoma. Another inhibitor, Flurbiprofen, enhanced the activity of chlorambucil on a chemo-resistant line of Walker tumor. The most widely studied method of reducing toxicity of antitumor agents has continued to be encapsulation in liposomes. The mechanism of drug toxicity reduction and pharmacokinetics of liposome encapsulated drugs has been reviewed in this chapter. A great deal of research has continued toward the goal of inhibiting carcinogenesis.

Chapter 13. Antineoplastic Agents

Publisher Summary A great deal of research continued to be stimulated by the clinical efficacy of compounds, such as cyclophosphamide, L-phenylalanine mustard (1-PAM), bis-chloroethyl nitrosourea, and close analogs as antineoplastic agents. With the development of chlororotocin and streptorotocin additional work has sought further decreases in the toxicity and advantages in activity profile. The absolute configuration of cyclophosphamide is obtained by x-ray diffraction and allows the determination of the absolute configuration at the phosphorus of all chiral metabolites of cyclophosphamide. The screening of compounds from fermentation and other natural sources continue to provide the greatest number of new antineoplastic agents. Two antibiotics structurally related to bleomycin, tallysomycin A and B are identified as having antitumor activity comparable to bleoniycin. Antitumor activity against a solid tumor in mice is studied for a new antitumor antibiotic, sporamycin. A group of fermentation-derived ansamycins, similar in structure to maytansine and active against a broad range of tumor systems, displayed strongest activity against P388 leukemia in mice at low daily doses. Activity against inurine P388 leukemia is also observed when treated with fatty acid containing 12-6 carbons, gycine, or β-alanine.