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PubMed1982

Generation of hydroxyl radical by anticancer quinone drugs, carbazilquinone, mitomycin C, aclacinomycin A and adriamycin, in the presence of NADPH-cytochrome P-450 reductase.

The generation of hydroxyl free radicals in the system consisting of purified NADPH-cytochrome P-450 reductase and anticancer quinone drugs, such as carbazilquinone, mitomycin C, aclacinomycin A and adriamycin, has been confirmed by two methods. In the spin trapping study, using N-tert-butyl-alpha-phenylnitrone as the spin trapping agent, four drugs generated hydroxyl radical-trapped signals, and the formation of the spin adduct was dependent on time and the enzyme concentration. Among the four drugs, the generation time of signal was in the order of carbazilquinone, aclacinomycin A, adriamycin and mitomycin C, but the magnitude of signal intensity was different. In both aclacinomycin A and adriamycin, the signal disappeared in a few minutes. Catalase completely inhibited the formation of the spin adduct, while superoxide dismutase did not significantly inhibit, but effected in some manner. The generation of hydroxyl radical was also confirmed by the ethylene production from methional. Among the four drugs, the order of the magnitude of ethylene production was different from that of signal intensity by ESR study. Catalase potently inhibited the ethylene production, while superoxide dismutase effected in some manner. From these results, the interactions of anticancer quinone drugs with NADPH-cytochrome P-450 reductase and oxygen, and the possible relations of the enzymes to the radical related actions of these drugs are discussed.

Aclarubicin↗

PubMed1991

Menadione: spectrum of anticancer activity and effects on nucleotide metabolism in human neoplastic cell lines.

The spectrum of cytotoxicity of menadione (MD) was examined in a panel of human cancer cell lines. MD was equipotent against multidrug-resistant and parental leukemia cell lines with IC50 values of 13.5 +/- 3.6 and 18 +/- 2.4 microM respectively. A cervical carcinoma cell line resistant to the antimetabolite, methotrexate (MTX), was as sensitive to MD as its parental cell line. The interactions of fifteen clinically utilized anticancer drugs with MD were examined in vitro and the majority were found to be additive, with four agents exhibiting synergism and one agent exhibiting antagonism. MD inhibited the incorporation of radioactive thymidine, uridine and amino acids into DNA, RNA and protein, respectively, in three human cancer cell lines. Some possible reasons for the inhibition of DNA synthesis including effects of MD on intracellular deoxyribonucleoside triphosphate pools were examined and ruled out. Although results from previous studies using rat hepatocytes suggested that mitochondria may be a target of MD, no significant effect of this compound on total intracellular adenosine triphosphate (ATP) pools in human cancer cell lines was observed. Collectively, these in vitro results demonstrate that MD possesses a broad spectrum of anticancer activity and suggest the potential utility of this agent in cancer therapy. Future studies directed at elucidation of the mechanism of MD action in human cancer cells are warranted and are under study.

Antineoplastic Agents↗

PubMed1993

Emetic effects of anticancer drugs and involvement of visceral afferent fibers and 5-HT3 receptors in dogs.

The emetic effects of five anticancer drugs, cyclophosphamide, nitrogen mustard-N-oxide, actinomycin D, 5-fluorouracil and L-asparaginase, and the effects of bilateral abdominal vagotomy and bilateral greater splanchnic nerve section or a 5-HT3 receptor antagonist on the emesis induced by these drugs were investigated in dogs. Cyclophosphamide (20 mg/kg, i.v.), nitrogen mustard-N-oxide (5 mg/kg, i.v.) and actinomycin D (50 micrograms/kg, i.v.) caused vomiting in dogs with a long latency period. 5-Fluorouracil (5 mg/kg, i.v.) and L-asparaginase (2000 K.U./kg, i.v.) failed to induce vomiting. Bilateral abdominal vagotomy and bilateral greater splanchnic nerve section completely inhibited the vomiting induced by the former three anticancer drugs. Furthermore, the vomiting was inhibited completely by intravenous administration of ICS205930 (2 x 0.1 mg/kg), a 5-HT3 receptor antagonist. These results suggest that activation of visceral afferents through 5-HT3 receptors mediates the vomiting induced by cyclophosphamide, nitrogen mustard-N-oxide and actinomycin D.

Animals↗

PubMed1989

Hydroxyl radical generation and DNA strand scission mediated by natural anticancer and synthetic quinones.

Using ESR and spin-trapping techniques, it was found that synthetic 2-dimethylamino-3-chloro-1,4-naphthoquinone and the natural anticancer quinone daunomycin, when added to a system containing purified NADPH-cytochrome P-450 reductase, NADPH, ferric ions, and oxygen, (i) generated hydroxyl radicals and (ii) caused single-strand scission of supercoiled DNA of the plasmic pBR322. Since these two effects of the quinones were correlated to each other, we propose that potential anticancer quinones can be effectively screened by measuring their ability to form hydroxyl radicals in the above system.

DNA Damage↗

PubMed1993

Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action.

Vitamin D is a membrane antioxidant: thus Vitamin D3 (cholecalciferol) and its active metabolite 1,25-dihydroxycholecalciferol and also Vitamin D2 (ergocalciferol) and 7-dehydrocholesterol (pro-Vitamin D3) all inhibited iron-dependent liposomal lipid peroxidation. Cholecalciferol, 1,25-dihydroxycholecalciferol and ergocalciferol were all of similar effectiveness as inhibitors of lipid peroxidation but were less effective than 7-dehydrocholesterol; this was a better inhibitor of lipid peroxidation than cholesterol, though not ergosterol. The structural basis for the antioxidant ability of these Vitamin D compounds is considered in terms of their molecular relationship to cholesterol and ergosterol. Furthermore, the antioxidant ability of Vitamin D is compared to that of the anticancer drug tamoxifen and its 4-hydroxy metabolite (structural mimics of cholesterol) and discussed in relation to the anticancer action of this vitamin.

Animals↗

PubMed1996

Use of principal component analysis for the study of the retention behaviour of anticancer drugs on a beta-cyclodextrin polymer-coated silica column.

The retention parameters of eighteen commercial anticancer drugs were determined on a beta-cyclodextrin polymer-coated silica support (beta CDP) using methanol-water mixtures as eluent and the relationship between the retention behaviour and physico-chemical parameters was elucidated by principal component analysis (PCA) followed by two-dimensional non-linear mapping. No significant linear correlation was found between the retention behaviour of drugs on octadecylsilica and beta CDP silica columns, indicating that the retention capacity and selectivity of the columns are considerably different. The results of PCA indicated that hydrophobic and electronic interactions and steric conditions govern the retention of anticancer drugs on beta CDP column, suggesting a mixed retention mechanism.

Antineoplastic Agents↗

PubMed1994

Effects of DNA adduct structure and distribution on the mutagenicity and genotoxicity of two platinum anticancer drugs.

cis-Diamminedichloroplatinum(II) (cis-DDP) and cis,trans,cis-ammine(cyclohexylamine)-dibutyratodichloroplatinu m(IV) (ACDDP) are anticancer drugs that bind to DNA, forming replication blocking adducts. ACDDP, probably manifests its cytotoxicity through the metabolite cis-ammine(cyclohexylamine)dichloroplatinum(II) (ACDP). The biological effects of ACDP and cis-DDP were compared by studying polymerase inhibition in vitro and mutagenesis and genotoxicity in vivo in the duplex genome of bacteriophage M13mp18 replicated in Escherichia coli. cis-DDP and ACDP adducts were equally genotoxic within the statistical error limits of the analysis. Survival of genomes platinated by either drug, increased by threefold in cells pretreated with u.v. irradiation to induce the SOS functions of the host. In the M13mp18 lacZ' gene fragment, the mutagenicity of ACDP was lower than that of cis-DDP; the difference was approximately twofold at a dose of two adducts per 370 base-pair mutational target. Mutagenesis by both compounds was SOS-dependent. The structural basis for lower mutagenicity of ACDP is proposed to be its reduced reactivity at d(ApG) sites. This effect is attributed to an orientational isomerism that precludes the formation of one of two possible DNA adducts at d(ApG) residues. The types of mutations induced for both drugs were similar, but they occurred with different distributions. Both compounds induced primarily G-->T transversions at d(GpG) sites whereas G-->A transitions and A-->T transversions, many at d(ApG), d(GpNpG), and d(GpG) sites, were also well represented. The mapping of DNA adducts by DNA synthesis inhibition revealed excellent correlation between the location of DNA lesions and the sites of mutations. Analysis of the distribution of mutations and the distribution of potential platination sites revealed no sequence-dependent mutation hotspots; i.e. mutagenesis was random throughout the lacZ' region of the M13mp18 bacteriophage genome. These results offer insights into the molecular mechanism of mutagenicity of platinum anticancer drugs.

Antineoplastic Agents↗

PubMed1986

The effects of acute administration of cytotoxic anticancer agents on the capacity for subsequent hormonal responses in the mouse uterus.

The mouse uterus has been used as a model system with which to examine the interaction of anticancer agents with steroid hormone receptors and to evaluate the effect of a single exposure to a cytotoxic anticancer agent on the subsequent elicitation of the uterotrophic response to estradiol. The uterotrophic response was interpreted in terms of the induction of progesterone receptors, uterine weight gain and increased uterine DNA content. Evaluation of 34 cytotoxic agents selected for this study provided little evidence to substantiate the interaction of these agents with estrogen or progesterone receptors. Although prior treatment with certain cytotoxic agents partially inhibited the subsequent responses to estradiol, some capacity to respond to estradiol was always retained. The majority of cytotoxic agents had little impact on the capacity to respond to estradiol. Thus, in these studies where high sublethal concentrations of cytotoxic agents were administered prior to estradiol, there was no indication that the mechanisms regulating subsequent hormonal responses were compromised.

Animals↗

PubMed1983

Carbinolamines and related structures--potential alkylating metabolites of clinically active anticancer drugs.

The precise biochemical mechanism by which a number of clinically-active anticancer compounds function remains unclear. Among these are procarbazine (NSC-77213), cyclophosphamide (NSC-26271), streptozotocin (NSC-85998), dacarbazine (NSC-45388), and hexamethylmelamine (NSC-13875). In all cases, there is an N-methyl or N-alkyl substituent which can be or has been shown to generate carbinolamine-like intermediates as a result of oxidative metabolism. Such intermediates can react with amines, imines, sulfhydryls and similar functional groups to form covalent linkages. Thus, carbinolamine metabolites of these clinically-active compounds are proposed as the active agents capable of altering covalently nucleic acids and proteins. It is this alkylating property that may be responsible for these compounds adversely effecting the mitosis of neoplastic cells. Thus, a unifying hypothesis is proposed whereby metabolic hydroxylation of various miscellaneous anticancer agents is the basis for biological activity. In essence, therefore, three broad classes of alkylating agents may be perceived: (1) the classical alkylators such as the nitrogen and sulfur mustards and the sulfonates, (2) bioreductive alkylating agents, and (3) biooxidative alkylating agents such as the carbinolamines. Though the chemical spectrum of each category may be highly diverse, nevertheless, all function as alkylating agents.

Alkylating Agents↗

PubMed1985

In the search for new anticancer drugs XII. Synthesis and biological evaluation of spin labeled nitrosoureas.

The spin labeled nitrosourea 1-(2-chloroethyl)-3-(1-oxyl-2,2,6,6- tetramethyl-piperidinyl)-1-nitrosourea (SLCNU, 4) and its analogues 5-7 were synthesized either by a regio-selective method or by a conventional route via the nitrosation of the spin labeled intermediates (11a-e). Nitrosation of the ureas 11a-e with dinitrogen tetraoxide resulted in better yields than those obtained with sodium nitrite. The nitrosoureas 4-8 were tested for their anticancer activity against the lymphocytic leukemia P388 in mice. Thus, either at the equal molar dose or at the dose of equal toxicity level, the SLCNU (4) was found to be more active than the clinically used CCNU (1). Unlike CCNU (1) whose LD50 is 56 mg/kg, the SLCNU (4) possesses a low toxicity (LD50 123 mg/kg). Therefore, SLCNU (4) is a promising new entry into the nitrosourea class of anticancer drugs.

Animals↗

PubMed1996

The clinical use of mutagenic anticancer drugs.

Cytotoxic chemotherapy is routinely used in the treatment of cancer, and has been an important factor in increasing 5-year survival rates for some types of this disease. A range of drugs are currently available, with differing modes of action. As well as causing some direct toxic effects, most if not all of these drugs are both mutagenic and carcinogenic. Although comparative information on these properties is generally available for anticancer drugs which alkylate DNA, it has been less readily accessible for other drug classes. This special issue contains seven reviews on the mutagenic properties of the major classes of cytotoxic drugs in clinical use, as well as one on a class of drugs that is under development. Some carcinogenicity data are also summarised, where available. Additionally, there are four more general papers, including one on the use of genetic activity profiles for comparing mutagenicity of the drugs, two on germ-cell effects, and one on biomonitoring for exposure to genotoxic anticancer drugs.

Adolescent↗

PubMed1996

Genetic activity profiles of anticancer drugs.

The results from short-term tests for genetic and related effects, abstracted from the open literature for 36 anticancer drugs, are examined in this review. Data for 27 of these agents are available in the EPA/IARC Genetic Activity Profile (GAP) database. Data summaries, including data listings and activity profiles, are presented for nine anticancer drugs added to the GAP database for this analysis. Genetic toxicity data from the recent literature are included for the additional agents to provide a broader representation of the categories of drugs being evaluated. These categories, based on the chemical mode of action, are covalent and noncovalent DNA-binding drugs, topoisomerase II inhibitors, antimetabolites, mitotic spindle inhibitors, and drugs which affect endocrine function. The qualitative data for all 36 drugs are summarized in this report and findings are presented from pair-wise matching of genetic activity profiles, based on test results in common, for some chemical analogs. The significance of germ cell test results for some of these drugs and their implication in assessing risk of heritable genetic disease are discussed.

Animals↗

PubMed1995

Investigation of chemoresistance-related genes mRNA expression for selecting anticancer agents in successful adjuvant chemotherapy for a case of recurrent glioblastoma.

BACKGROUND: Glioblastoma multiforme represents one of the most malignant forms of primary intracranial tumors, often intractable to multimodality of treatment including chemotherapy. The unsatisfactory results of chemotherapy are chiefly attributed to chemoresistance. Since various molecules that could confer drug resistance have been elucidated, screening of the amount of such molecules in the tumor cells could provide possibilities for predicting their chemoresistance beforehand and help select more effective drugs. METHODS: We present a 45-year-old woman with recurrent glioblastoma multiforme in the cerebellum and invading the brain stem, treated successfully by postoperative chemotherapy. In this patient, anticancer drugs were determined by measurements of mRNA expression of chemoresistance-related genes, such as O6-methylguanine-DNA methyltransferase (MGMT), mdr1, glutathione S-transferase (GST)-pi, and metallothionein (MT) in the resected tumor. RESULTS: Northern blot analysis demonstrated the moderate mRNA level of MGMT, a major molecule causing ACNU (1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitroso ure a hydrochloride) resistance. On the other hand, expression levels of mdr1 which codes the P-glycoprotein responsible for multidrug resistance, and GST-pi, a detoxification enzyme, were low. Transcript of MT, another thiol containing molecule for cellular detoxification possibly associated with cisdiamminedichloroplatinum(II) (CDDP) resistance, was only faintly detectable. Postoperatively, the patient was treated initially with intravenous administration of ACNU and etoposide (VP16), resulting in a minor response of tumor regression. For maintenance therapy, we changed ACNU to CDDP according to the findings of the Northern blot analysis. Consequently, the residual tumor showed a marked response and almost disappeared after two courses of systemic chemotherapy with CDDP and VP16. CONCLUSIONS: The successful tumor regression in this case suggests that Northern blot analysis on expression of these chemoresistance-related genes in tumor tissues could provide beneficial information for determination of optimal anticancer agents to improve the efficacy of chemotherapy.

Antineoplastic Agents↗

PubMed1986

Absorption of anticancer drugs through bladder epithelium.

Fundamental and clinical evaluations of ten anticancer drugs were performed. The required qualities of an anticancer drug ideal for bladder instillation therapy are thought to be as follows: (1) a high sensitivity for bladder tumor cells; (2) a pKa which provides a high percentage of nonionized molecules in a pH 6-7 solution; (3) a log P in the range from -0.4 to -1.2 or from -7.5 to -8.0; and (4) a molecular weight over 200.

Absorption↗

PubMed1993

Dinuclear complexes of platinum having anticancer properties. DNA-binding studies and biological activity of bis(4,4'-dipyrazolylmethane-N,N')- bis[dichloroplatinum(II)] and related complexes.

Some DNA-binding experiments employing a selected number of novel dinuclear platinum complexes with the 4,4'-dipyrazolylmethane (dpzm) ligand are reported. A DNA-cleavage assay using Eco RI and Bam HI restriction endonucleases to probe the binding of the complexes at or near their unique restriction sequences of pUC9 DNA has been examined. The complex beta-[Cl2Pt(dpzm)2PtCl2] has a greater affinity for DNA at the Eco RI restriction sequence over the Bam HI site. To our knowledge, the preferential inhibition of Eco RI activity is unprecedented for any platinum species reported to date. Further, the dinuclear complexes beta-[Cl2Pt(dpzm)2PtCl2], beta-[Cl4Pt(dpzm)2PtCl4] x 0.5dmf x 0.5H2O and [Cl4Pt(dpzm)2PtCl2] are capable of inhibiting Eco RI activity to a far greater extent than the platinum anticancer drug cis-[PtCl2(NH3)2] (cisplatin). The in vivo and in vitro anticancer properties of some of the platinum complexes are also described. The complexes alpha-[Cl2Pt(dpzm)2PtCl2] x 0.5dmf and beta-[Cl2Pt(dpzm)2PtCl2] display significant activity against P388 lymphocytic leukemia in mice.

Animals↗

PubMed1990

Role of the glutathione-glutathione peroxidase cycle in the cytotoxicity of the anticancer quinones.

Recent studies have suggested that the selenoenzyme glutathione peroxidase, in the presence of reducing equivalents from the tripeptide glutathione, is responsible for detoxifying hydrogen peroxide and lipid hydroperoxides generated as a consequence of the cyclic reduction and oxidation of quinone-containing anticancer agents including doxorubicin, daunorubicin, mitomycin C, diaziquone, and menadione. Alterations in the intracellular levels of glutathione peroxidase or glutathione can significantly affect the activity of these drugs against human tumor cells and the expression of their normal tissue toxicity, especially with respect to the heart. Furthermore, augmentation of the glutathione peroxidase pathway appears to render certain human tumor cells relatively resistant to the anticancer quinones; therefore, the glutathione peroxidase system may, at least in part, modulate certain forms of acquired drug resistance in man. Thus, the glutathione peroxidase cycle appears to play a central role in maintaining intracellular peroxide homeostasis during quinone-induced oxidative stress.

Animals↗

PubMed1986

Mutagenicity of the anticancer drug, caracemide, and related compounds for salmonella.

Caracemide, MeCON(CONHMe)(OCONHMe) (I), is a novel anticancer drug. Since it was derived from acetohydroxamic acid (II), a known mutagen, its potential metabolites and related compounds were synthesized and tested for mutagenicities in S. typhimurium TA98 and TA100. These compounds were: MeNHCONH(OCONHMe) (III), MeCONH(OCONHMe) (IV), MeCONOH(CONHMe) (V), MeNHCOONH2 X HCl (VI), MeNHCONHOH (VII), MeNHCOON(CONHMe)2 (VIII), and NOH(CONHMe)2 (IX). The mutagenicities in the absence of rat liver homogenate were: (VI) much greater than (IV) greater than (II), (III), (V). The other compounds were not mutagenic. (I) was mutagenic only in the presence of rat liver homogenate. The doses required to demonstrate mutagenicities of these compounds were from 0.05 to 5 mumoles/plate. The major hydrolytic products at 25 degrees C, pH 7, were (III), (IV), and (V) from (I); (II) and (III) from (IV); and (II), (III), (VII) and MeNHCONH(OCOMe) (X) from (V). (III) was stable at pH 7. Treatment of (IV) with HCl yielded (VI). Hydrolysis of (III) or (V) with ammonia yielded (VII). These results suggest that caracemide may be activated enzymatically or nonenzymatically by deacetylation or decarbamoylation, and its anticancer activity may be related to the reactivity of its metabolites with DNA. The synthetic procedures and characterizations of new compounds (IV), (V) and (X) are described.

Animals↗

PubMed1991

Effect of anticancer drugs on the release of interleukin-3 in vitro.

In this study several anticancer drugs were tested for their effect on the release of interleukin-3 (IL-3) from concanavalin A (Con A) stimulated mouse splenocytes in vitro. When Adriamycin or vincristine were added to the cultures at non-cytotoxic concentrations, the release of IL-3 was inhibited. However, bleomycin, FK156, FK565 and 4-OOH-cyclophosphamide (the in vitro active analogue of the anticancer and immunosuppressive drug cyclophosphamide) did not alter the release of IL-3 under the same conditions. It was confirmed that cyclosporin A inhibited the release of IL-3 in the same experimental system.

Animals↗