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PubMed1989

Changes in serum copper and zinc during treatment with anticancer drugs interfering with pyridoxal phosphate.

Hexamethylmelamine, pentamethylmelamine and procarbazine are anticancer drugs known to interfere with pyridoxal phosphate. This paper presents results on copper and zinc serum levels during the treatment with each of these drugs used as single agents. Six NZW rabbits weighing 2.7-4.5 kg were used in these experiments. Hexamethylmelamine and procarbazine were administered by gastric gavage and pentamethylmelamine by intravenous route at the daily doses of 100 mg, 30 mg and 50 mg/kg of body weight respectively for up to four days. Blood samples were collected in metal free tubes at fasting state before and during the treatment. Student's paired t-test was used for statistical analysis. The pretreatment serum copper concentration significantly (p = 0.05) increased and conversely the serum zinc concentration significantly (p = 0.05) decreased during each drug treatment. Consequently the copper/zinc ration significantly increased from 0.32, 0.33 and 0.27 to 1.16, 0.63 and 1.13 for hexamethylmelamine, pentamethylmelamine and procarbazine respectively. These results indicate, that daily administration of three anticancer drugs interfering with pyridoxal phosphate causes changes in serum copper and zinc levels with inversed relationship between both changes.

Altretamine↗

PubMed2000

Molecular events that regulate cell proliferation: an approach for the development of new anticancer drugs.

Cancer chemotherapy is the object of many fundamental and clinical researches. The development in molecular techniques and structural studies at the molecular level have led to the discovery of key proteins involved in the regulation of cell proliferation. This opened perspectives to characterize new anticancer drugs in order to reduce the limitations found with conventional drugs such as the lack of selectivity for cancer cells and resistance phenomena. This review presents the anticancer drugs in clinical investigations that target molecules involved in the signal transduction impairment, the cell cycle deregulation and the differentiation with comments on their mechanisms of action.

Antineoplastic Agents↗

PubMed1992

Assessing and counteracting the prooxidant effects of anticancer drugs.

The relationship between peroxide generation and respective cellular damage, triggering various biochemical consequences is first discussed. Then we review the prooxidant effects of various anticancer drugs including anthracyclines and bleomycin, platinum derivatives and the N- and S-mustards. We present and discuss some experimental results on peroxidase inhibition by drugs such as zinc salts, almitrine, deferoxamine, which had previously been tested as efficient in vivo treatment on chlormethine intoxication. In an overview we propose that not only ionizing radiations and anticancer drugs, but also promoters and initiators of cancer might all generate free radicals, in turn triggering oxidative processes generating endogenous peroxides, then probably amplifying the deleterious biological response. The possible limitations of drug therapies decreasing peroxide generation are presented.

Alkylating Agents↗

PubMed1980

Comments on the carcinogenic, mutagenic, and teratogenic properties of anticancer drugs.

Relevance of the carcinogenic effects of anticancer agents has arisen in the context of three circumstances: (a) when patients who have a favorable outlook without treatment receive chemotherapy, (b) when several alternate therapies with varying carcinogenic potential are available, and (c) when considering the introduction of a new drug into clinical investigation and/or clinical practice. Teratogenic effects require special attention when dealing with women in their reproductive years. Techniques to evaluate the mutagenic effects have opened up new areas of research and will be increasingly applied to the study of anticancer drugs.

Antineoplastic Agents↗

PubMed1987

Biological and biochemical properties of new anticancer folate antagonists.

We review the biology and biochemical pharmacology of four antifolates that were recently introduced into clinical trial as anticancer agents, and one compound in preclinical development. Toxicology and clinical data are not discussed. 10-Ethyl-10-deazaaminopterin (10-EdAM) is a classical antifolate, structurally related to methotrexate (MTX) but with greater activity against murine tumors. 10-EdAM has more efficient membrane transport, and relatively greater polyglutamylation in murine tumors than in normal mouse tissues, and these differential effects are greater for 10-EdAM than for other 10-deaza antifolates or for MTX. Trimetrexate and piritrexim are nonclassical antifolates, lacking a glutamate substitution. They are lipophilic, cross cell membranes more rapidly than does MTX, and retain activity against tumors resistant to MTX because of impaired drug transport. These nonclassical antifolates are active against several MTX-insensitive murine tumors, and both have demonstrated clinical anticancer activity. 10-EdAM, trimetrexate and piritrexim all inhibit dihydrofolate reductase (DHFR) as their primary site of action. As such, they deplete cellular thymidylate and purine pools, and inhibit DNA replication. N10-Propargyl-5,8-dideazafolic acid (CB3717) differs from the first three compounds in acting primarily on thymidylate synthase. Like DHFR inhibitors, it blocks DNA replication through depletion of dTTP, but it does not exert an antipurine effect. CB3717 retains activity against transport-defective MTX-resistant cells, and also against cells that overproduce DHFR. 5,10-Dideazatetrahydrofolic acid (DDATHF) is a selective inhibitor of glycinamide ribotide transformylase, and its biochemical pharmacology may differ appreciably from that of the other antifolates under study. DDATHF has strong antitumor activity in several murine systems.

Animals↗

PubMed1993

Development of lipophilic anticancer agents for the treatment of brain tumors by the esterification of water-soluble chlorambucil.

The lipophilic derivatives of the anticancer alkylating agent chlorambucil, chlorambucil-methyl, -isopropyl and -tertiary butyl esters, were synthesized and administered i.v. to anesthetized rats. Plasma and brain concentrations of these agents and of their active metabolites, chlorambucil and phenylacetic mustard, then were determined by high-performance liquid chromatography between 5 and 60 min. Whereas large amounts of chlorambucil-tertiary butyl ester entered and were maintained in brain, lower amounts of chlorambucil-isopropyl ester and no chlorambucil-methyl ester were found in brain. The comparative brain/plasma concentration-time integral ratios of the total active agents generated from chlorambucil-tertiary butyl, -isopropyl and -methyl esters were 0.85, 0.12 and 0.06, respectively, compared to a ratio of 0.02 for chlorambucil. In vitro alkylating activity of each ester was compared to that of equimolar chlorambucil, by reaction with 4-(p-nitrobenzyl)pyridine. Each ester possessed high intrinsic alkylating activity, equal to 38.4, 57.0 and 69.9% of chlorambucil activity, for the -tertiary butyl, -isopropyl and -methyl esters, respectively. Therefore each is an active antineoplastic agent irrespective of whether or not chlorambucil is regenerated. The rates of ester hydrolysis of these derivatives to chlorambucil were measured in fresh rat blood and in liver and brain homogenates at 37 degrees C. Chlorambucil-methyl and -isopropyl esters were hydrolysed quickly within 30 s in blood and liver, whereas chlorambucil-tertiary butyl ester was more stable with half-lives of approximately 7 h and 2 h, respectively. All proved to be relatively stable in brain homogenate. Steric hindrance around the ester linkage of chlorambucil-tertiary butyl ester reduces its affinity to and rate of hydrolysis by plasma and liver esterases, and allows it to accumulate within the brain. Chlorambucil-tertiary butyl ester maintains high levels in brain despite rapidly declining plasma concentrations and, due to these favorable pharmacokinetics and to its intrinsic anticancer activity, it possess promising characteristics for the treatment of malignant brain tumors.

Alkylating Agents↗

PubMedDate not supplied

Metrazol enhances brain penetration and therapeutic efficacy of some anticancer agents: implications for brain metastases.

The concurrent administration of Metrazol (60 mg/kg, i.v.) to anaesthetized rats enhances the cerebral penetration of the anticancer agent razoxane. Such an enhancement leads to an increase in the therapeutic efficacy of razoxane against intracerebrally sequestered L1210 leukaemia cells in mice. The combination of Metrazol and melphalan was also examined to see if the concentration of other anticancer agents in CSF could be enhanced.

Animals↗

PubMed1983

Heterogeneous responses of an in vitro model of human stomach cancer to anticancer drugs.

Four permanent clones of a human adenocarcinoma of the stomach and the parent line from which they were isolated were used as an in vitro model system to evaluate the effects of 8 anticancer agents on cell survival. The drugs tested were actinomycin D (Act-D), Bleomycin (Bleo), adriamycin (adria), melphalan, chlorambucil, 5 Fluorouracil (5FU), 1,2:5,6-Dianhydrogalactitol (DAG), and 1-(2-chloroethyl)-3-(4-methyl cyclohexyl-1-nitrosourea) (MeCCNU). Although the cell lines had similar growth properties, morphologies and modal chromosome numbers, the clones expressed heterogeneous survival responses to each of six drugs tested. A comparison of the doses lethal to 90% of a clonal population (LD90) for each drug indicated large differences between the most sensitive and least sensitive clones. For chlorambucil there was a 160% difference between the LD90 values of the most and least sensitive clones. For MeCCNU the difference was 200%; for adria, 230%; Bleo, 280%; 5FU, 360%; and melphalan, 600%. Despite the heterogeneity in response among the clones to these agents, no particular clone was always the most sensitive or resistant. Of particular interest was the finding that these stomach cancer clones demonstrated uniform responses to both Act-D and DAG. Since the differential drug sensitivities expressed by heterogeneous tumor populations could be a cause of treatment failure in the patient, the demonstration of uniform sensitivities to Act-D and DAG are encouraging and suggest that other anticancer drugs which produce uniform cell killing may be identified and tested. Act-D and adria were the most effective of the drugs tested when compared on a dose for dose basis. Both agents killed more than 99.9% of the parent cell line with doses below 3 micrograms/ml (1-h treatments). The cells were least sensitive to 5FU, with only 30% of the cells killed at 100 micrograms/ml. The studies reported here indicate that this human stomach cancer model can provide valuable insight into the design of clinical protocols for treatment of gastric carcinoma in man.

Adenocarcinoma↗

PubMed1985

The synergistic tumoricidal activity of anticancer drugs and oxidative burst-triggered macrophages.

The anticancer drugs adriamycin (ADR) and actinomycin D (AMD) were tested for their effect on the oxidative burst (OB) of mouse peritoneal macrophages (MPM) and on the killing of tumor cells by OB-stimulated MPM. The oxidative burst of MPM determined by hydrogen peroxide (H2O2) production was severely impaired by ADR (10 micrograms/ml) and AMD (40 micrograms/ml) after a 1 h treatment and by lower concentrations of the drugs following a 24 h treatment. The toxicity of the drugs against MPM was comparable to their effect on EL4 cells. Pretreatment of EL4 and TLX-9 tumor cells with sublethal amounts of ADR for 4 h rendered the cells sensitive to the cytotoxic effect of OB-stimulated MPM which were otherwise unable to kill these cells. It seems that anticancer drugs and OB-stimulated macrophages can cooperate in the destruction of tumor cells in vitro.

Animals↗

PubMed1979

Physiologically based pharmacokinetic models for anticancer drugs.

The rationale and history of the development of physiologically based pharmacokinetic models are briefly reviewed in this paper. The methods of model construction and the previous application of this type of model to anticancer drugs are discussed. Future research should be focused on the following areas: (1) interspecies scaling, (2) the effects of disease states on the pharmacokinetics of anticancer drugs, and (3) the applications of pharmocokinetics to the studies of growth behavior of cancer cells. The ultimate goal will be to utilize this basic information to design an optimal dosage regimen and treatment schedule for the safe and effective cancer chemotherapy of each individual patient.

Ancitabine↗

PubMed1986

In vivo and in vitro anticancer activity of the structurally novel and highly potent antibiotic CI-940 and its hydroxy analog (PD 114,721).

CI-940, PD 114,721, and PD 118,607 are structurally novel antibiotics, which were isolated from fermentation beers of a previously unknown actinomycete. They are highly lipophilic acids characterized by unsaturated lactone and branched, polyunsaturated aliphatic side-chain moieties. All three agents demonstrated significant cytotoxic activity in vitro against a number of human and mouse tumor lines which encompassed a wide range of tissue types. CI-940 retained full activity in vitro against lines of P388 leukemia that are resistant to Adriamycin, amsacrine, and mitoxantrone. Activity was confirmed for both CI-940 and PD 114,721 against a number of murine experimental tumor systems in vivo, which included the P388 and L1210 leukemias and also B16 melanoma, Ridgway osteogenic and M5076 sarcomas, and mammary adenocarcinoma 16/C. PD 118,607 was also highly active against B16 melanoma. All three agents demonstrated anticancer activity at very low dosages compared with current clinically useful anticancer agents. No significant activity was seen against the MX-1 human mammary xenograft or pancreas 02 tumor models. The primary target for host toxicity of CI-940 and PD 114,721 appeared to be gastrointestinal in nature. Neither CI-940 nor PD 114,721 caused delayed lethality when given either IP or IV. In schedule studies, the toxicities of both CI-940 and PD 114,721 were moderately dependent on the regimen used, with total maximum tolerated dosages for intermittent (q4dx2), daily (qdx5), and divided daily (q4hx3, qdx5) dosing schedules of 1, 0.25, and 0.12 mg/kg, respectively. CI-940 is being developed for clinical trial on the basis of its potent activity against seven different tumor models, its novel structure, and its apparently novel mechanism of action.

Animals↗

PubMed1986

The mouse as a model for predicting the myelosuppressive effects of anticancer drugs.

We evaluated 17 clinically used anticancer drugs for their effects on total WBC and absolute neutrophil counts in BDF1 mice. These drugs were selected from three categories, based on their myelosuppressive effects in man: myelosuppression is dose-limiting; myelosuppression occurs but is not dose-limiting; or myelosuppression does not occur. The ability of each drug to cause myelosuppression in mice was determined by its effect on the neutrophil count 4 days after single-dose treatment. The neutropenic effect of the maximum tolerated dose (LD0-20) of each drug was characterized as marked (greater than 65% decreases), moderate (35%-65% decreases), or minimal (less than 35% decreases) to correspond with the three clinical categories of myelosuppression. The neutropenic effects in mice correctly predicted (true + or true -) the myelosuppressive effects in man for 13 of the 17 drugs (76%). Marcellomycin and the platinum complexes cisplatin, carboplatin, and spiroplatin did not cause neutropenia at maximum tolerated doses. These represent false-negative predictions, since the drugs are myelosuppressive in man. The results with the platinum complexes indicate that this method is not suitable as a means of screening these agents for myelosuppression. Excluding the platinum complexes, the predictions were correct for 12 of 13 drugs (92%). Therefore, this model is considered a good predictor for the myelosuppressive effects of anticancer drugs in man (except platinum complexes) and can be used effectively to screen drugs for this toxicity. However, it is important that drugs identified by this system as being less myelosuppressive than the reference agent(s) be evaluated further, since all the incorrect predictions were false negatives.

Animals↗

PubMed1986

Comparison of the pharmacokinetics and protein binding of the anticancer drug, amsacrine and a new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenyl-amino] -4-acridinecarboxamide in rabbits.

Amsacrine (NSC 249 992) is a new anticancer drug which, although effective for the treatment of various disseminated tumors, has shown disappointing activity against most solid tumors. A new analogue, N-5-dimethyl-9-[(2-methoxy-4-methylsulfonylamino)phenylamino] -4-acridine-carboxamide (CI-921, NSC 343 499) has been identified, which might offer a broader clinical antitumor spectrum. This analogue is more lipophilic (0.5 log p units) and is also a considerable weaker base (pKa 6.40) than amsacrine (pKa 7.43). This study compared the pharmacokinetics of total and unbound amsacrine and CI-921 in plasma after equimolar dose infusions (12.7 mumol/kg) in a balanced crossover design in six rabbits. Drug concentrations were determined by high-pressure liquid chromatography and the unbound fraction by equilibrium dialysis. Threefold higher total plasma concentrations were achieved with CI-921 than with amsacrine. However, the unbound fraction was significantly less for CI-921 (0.33% +/- 0.04) than for amsacrine (2.78% +/- 0.53). There was no significant difference between distribution and elimination half-life and mean residence time, but the apparent volume of distribution (means, 121 vs 45 l/kg) and clearance (means, 46.6 vs 16.3 l h-1 kg-1) of unbound CI-921 were threefold greater than the corresponding parameters for unbound amsacrine. We suggest that despite higher binding in plasma, the greater distribution or tissue uptake of CI-921 may be partly responsible for its greater anticancer activity in vivo.

Aminoacridines↗

PubMed1992

A novel anticancer treatment for xenoplanted human gastric cancer using polyamine antimetabolites in a low polyamine diet.

The aim of the present study was to evaluate a new anticancer treatment for gastrointestinal cancer, using a combination of polyamine antimetabolites, an anticancer agent and a low-polyamine state. Two polyamine antimetabolites, given as either 40 mg/kg of methylglyoxal-bis-guanylhydrazone (MGBG) or ethylglyoxal-bis-guanylhydrazone (EGBG) and a normal diet (ND), or 20 mg/kg of each drug and a low polyamine diet (LPD), together with 1,000 mg/kg of alphadifluoromethylornithine (DFMO) were administered ip to nude mice for six consecutive days. Mitomycin C (MMC) at 2 mg/kg was then given ip for 3 alternate days. The combination of MGBG or EGBG with DFMO plus MMC resulted in an enhanced antitumor efficacy on LPD. However, the combination which included EGBG was much more enhanced than that which included MGBG and there was no evidence of any tumor regrowth. Weight loss was minimal or nil in the mice given the combination with EGBG, but was evident in those given the combination with MGBG. These results led to the conclusion that in mice, the combined therapy of EGBG with DFMO plus MMC and LPD is a safe and effective regimen for the treatment of gastric cancer.

Adenosylmethionine Decarboxylase↗

PubMed1995

Intensive care in anticancer centres: an international inquiry.

Intensive care is increasingly frequently used in the management of cancer patients. In order to determine whether and how critical-care facilities are used specifically for these patients, we performed a world-wide inquiry in anticancer centres. We mailed a questionnaire to 141 centres and received 84 responses (57.5%). There was at least one oncological intensive care-unit (ICU) in 59 hospitals (70%). The majority of the ICU were found in the European institutions. Data were obtained concerning the ICU organisation, the medical team, the nursing staff, the critical-care techniques and the anticancer treatments performed. Medical ICU appeared to be managed by physicians and nurses often qualified in both intensive care and oncology. These data suggest that oncological intensive care should be part of the training of oncologists and intensivists.

Cancer Care Facilities↗

PubMed1991

Chromatographic characterisation of six human metabolites of the new anticancer drug GR63178A.

GR63178A is the second pentacyclic pyrroloquinone to enter clinical trials as an anticancer drug. We developed a reversed-phase, gradient-elution high-performance liquid chromatography (HPLC) method along with a Bond Elut C2 mini-column sample-preparation technique for the analysis of GR63178A, its 9-hydroxy-metabolite GR54374X and internal standard GR70440A in human plasma and urine. The limit of detection is 2 ng/ml for both GR63178A and GR54374X. Analysis of GR63178A is complicated by its light instability, whereby a number of chromatographically distinct, stable degradation products can form. These can be practically eliminated if clinical specimens are frozen immediately and all subsequent sample preparation is performed in a darkroom. Using this methodology, a total of six metabolites (including GR54374X) were detected in human plasma and urine specimens. The five new metabolites were characterised according to polarity (HPLC retention time), UV-visible absorption maxima and the effect of incubation with beta-glucuronidase and aryl-sulphatase. Application of this methodology to the analysis of GR63178A will aid in the development of this novel synthetic anticancer drug.

Antineoplastic Agents↗

PubMed1994

In vivo modulation of several anticancer agents by beta-carotene.

The ability of the collagenase inhibitor minocycline and of beta-carotene to act as positive modulators of cytotoxic anticancer agents was assessed in vitro and in vivo. Cell-culture studies were conducted using the human SCC-25 squamous carcinoma cell line. Simultaneous exposure of the cells to minocycline and beta-carotene or 13-cis-retinoic acid along with cisplatin (CDDP) resulted in a small decrease in the cytotoxicity of the CDDP. The addition of each of the modulator combinations for 1 h or 24 h to treatment with melphalan (L-PAM) or carmustine (BCNU) resulted in greater-than-additive cytotoxicity with each of four regimens. The modulator combinations of minocycline and beta-carotene applied for 1 h or 24 h and the modulator combination of minocycline and 13-cis-retinoic acid produced greater-than-additive cytotoxicity at 50 microM 4-hydroperoxycyclophosphamide (4-HC), whereas minocycline and 13-cis-retinoic acid applied for 1 h was antagonistic with 4-HC and the other modulator treatments at low concentrations of 4-HC resulted in subadditive cytotoxicity. The effect of treatment with beta-carotene alone and in combination with several different anticancer agents was examined in two murine solid tumors, the FSaII fibrosarcoma and the SCC VII carcinoma. Administration of the modulators alone or in combination did not alter the growth of either tumor. Whereas increases in tumor growth delay occurred with the antitumor alkylating agents and beta-carotene and with minocycline and beta-carotene, a diminution in tumor growth delay was produced by 5-fluorouracil in the presence of these modulators. The modulator combination also resulted in increased tumor growth delay with adriamycin and etoposide. Tumor-cell survival assay showed increased killing of FSaII tumor cells with the modulator combination and melphalan or cyclophosphamide as compared with the drugs alone. These results indicate that further investigation of this modulator strategy is warranted.

Animals↗

PubMed1994

Therapeutic response and potential pitfalls in phase I clinical trials of anticancer agents conducted in Japan.

The published reports of phase I clinical trials of anticancer agents conducted in Japan from 1981 to 1991 were reviewed. A total of 56 clinical studies that evaluated 38 different agents were reviewed. An average of five agents were studied each year. A total of 2200 patients had been recruited into the 56 clinical trials conducted during this period. A total of 91 patients (4.1%) responded to the treatment, with 23 showing a complete response (1.1%) and 48, a partial response (2.2%). In all, 62% of the responses were observed when patients were treated with doses ranging from 76% to 125% of the recommended doses for phase II studies. The response rates obtained for hematological malignancies were higher than those reported for other malignancies. The past status of phase I clinical trials in Japan can be summarized as follows. (1) A median of seven institutes participated in a single trial. The number of institutes participating correlated with the number of patients enrolled. However, too many institutes participated in a single phase I clinical trial in some studies. (2) The median duration of study for the clinical trials was 14 months. The duration of study was too long in some studies, considering the small number of patients enrolled. In conclusion, the methodology of phase I clinical trials of anticancer agents conducted in Japan should be improved in an efficient and scientific manner, especially for the testing of imported agents.

Antineoplastic Agents↗