ABSTRACT
The activity of 4-demethoxy-3'-deamino-3'-aziridinyl-4'-methylsulphonyl-daunorubicin (PNU-159548), a new alkycycline with high antitumor activity against a broad range of cancer cells, was evaluated in vitro and in vivo in cells selected for resistance to different anticancer agents. Both in vitro and in vivo, PNU-159548 did retain its activity in cells expressing the multidrug resistance (MDR) phenotype, associated to MIDR-1 gene overexpression or with an alteration in the topoisomerase II gene (altered MDR), independently on the drug used for the selection of the resistant cell line. According to these data, the intracellular uptake of PNU-159548 is not influenced by the presence of MDR-1. PNU-159548 was also active, both in vitro and in vivo, against cells showing resistance to various alkylating agents iincluding cisplatin, cyclophosphamide, and melphalan) and topoisomerase I-inhibitors. Cells defective in nucleotide excision repair, which did show hypersensitivity to treatment with UV irradiation and alkylating agents, showed only a marginally increased sensitivity to PNU-159548. Similarly, the activity of the drug was not influenced by the mismatch repair system, as assessed in two different cellular systems deficient in hMLH1 expression and in which hMLH1 activity was restored by chromosome 3 transfer. The results obtained clearly indicate that the new anticancer agent PNU-159548 is able to overcome the classical mechanisms of resistance emerging after treatment with the most clinically used anticancer agents, and it could represent an alternate choice in the treatment of those tumors refractory to conventional therapy.
Subject(s)
Antibiotics, Antineoplastic/pharmacology , Daunorubicin/pharmacology , Tumor Cells, Cultured/drug effects , Animals , CHO Cells , Cricetinae , Daunorubicin/analogs & derivatives , Drug Resistance, Neoplasm , Drug Screening Assays, Antitumor , Female , Humans , Inhibitory Concentration 50 , Leukemia L1210/drug therapy , Leukemia P388/drug therapy , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred DBAABSTRACT
FCE 26644, or 7,7'-(carbonyl-bis[imino-N-methyl-4, 2 pyrrole carbonyl-imino(N-methyl-4,2-pyrrole)carbonyl-imino])-bis-(1,3- naphthalene)disulfonic acid, belongs to the newly synthesized class of sulfonated derivatives of distamycin A. FCE 26644 is a noncytotoxic molecule capable of inhibiting the binding of basic fibreblast growth factor (bFGF), platelet-derived growth factor (PDGF beta) and interleukin 1 (IL-7) to their receptors and to block bFGF-induced vascularization in vivo as well as neovascularization in the chorioallantoic membrane. FCE 26644 and suramin, a compound possessing the same terminal half-life (t1/2) in mice and, presumably, the same mode of action, inhibit the growth of solid murine tumors, M5076 reticulosarcoma, and MXT and S180 fibrosarcoma and are inactive against B16F10 melanoma. The activity of FCE 26644 was constantly observed at nontoxic doses, at variance with suramin. FCE 26644 was also found to maintain activity against M5076 resistant to cyclophosphamide and to be equally active against UV 2237 and UV 2237/ADR fibrosarcoma.
Subject(s)
Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Distamycins/pharmacokinetics , Distamycins/therapeutic use , Fibrosarcoma/drug therapy , Lymphoma, Large B-Cell, Diffuse/drug therapy , Melanoma, Experimental/drug therapy , Animals , Cyclophosphamide/therapeutic use , Drug Administration Schedule , Drug Resistance , Female , Fibroblast Growth Factor 2/antagonists & inhibitors , Half-Life , Male , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Inbred DBA , Suramin/pharmacokinetics , Suramin/therapeutic useABSTRACT
The effect of suramin on B16F10 melanoma lung colonies and M5076 reticulosarcoma liver metastasis formation was evaluated in C57B1/6 female mice. Single i.v. doses of 200 mg/kg suramin given 48 and 24 h prior to tumor cell injection significantly inhibited metastasis formation in both models, whereas the same treatment administered 24 h after cell injection was ineffective. A dose-response experiment in the B16F10 melanoma model showed that inhibition of lung colony formation was still significant with 50 mg/kg pretreatment, whereas a borderline effect was observed at 10 mg/kg. At the effective doses, the plasma and organ concentrations of suramin were far below those needed to exert significant in vitro cytotoxic or cytostatic effects on B16F10 and M5076 cells. Thus, in addition to the antineoplastic effect of suramin our results indicate a potential antimetastatic role for this compound.
Subject(s)
Liver Neoplasms/drug therapy , Liver Neoplasms/secondary , Lung Neoplasms/drug therapy , Lung Neoplasms/secondary , Lymphoma, Large B-Cell, Diffuse/drug therapy , Melanoma, Experimental/drug therapy , Melanoma, Experimental/secondary , Suramin/pharmacology , Animals , Dose-Response Relationship, Drug , Female , Mice , Mice, Inbred C57BL , Suramin/pharmacokinetics , Tumor Cells, CulturedABSTRACT
The benefits of exercise are well established but the impact of exercise on the older adult is not as clearly defined. Increasing numbers of people in the United States are over 65 years old. Thus health care providers will find themselves often involved with the older adult and will need an understanding of exercise in this age group. This article reviews the known benefits of exercise for the older adult, exercise-related age changes, and how to prescribe exercise for those 65 years and over. Selected case reports are used to provide examples of how specified guidelines can be incorporated into practice.
