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PubMed1993

Inhibitory effects of anticancer drugs on dextromethorphan-O-demethylase activity in human liver microsomes.

The dextromethorphan-O-demethylase activity determined in human liver microsomes was used to screen various anticancer drugs for their ability to inhibit this cytochrome CYP2D6-dependent activity. Competitive inhibition indicates that the drug binds the enzyme and is potentially subjected to a polymorphic metabolism. Among the 13 anticancer drugs tested, 4 compounds caused competitive inhibition of dextromethorphan-O-demethylation: lomustine (Ki = 7.7 microM), doxorubicin (Ki = 75 microM), vinorelbine (Ki = 22 microM), and vinblastine (Ki = 42 microM). The results of these studies indicate that the metabolism of the drugs concerned is possibly altered in poor metabolizers of debrisoquine and requires further investigation to study their specific routes of biotransformation. The metabolism of these drugs probably involves various biotransformation pathways, among which the CYP2D6-dependent route would be of minor importance. A second hypothesis is that these drugs could be inhibitors of the isozyme without being a substrate.

Antineoplastic Agents↗
PubMed1994

Relation between age and clearance rate of nine investigational anticancer drugs from phase I pharmacokinetic data.

Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21-77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (< 65 or > 65 years) versus dose delivered [< the maximum tolerated dose (MTD) vs > or = the MTD] or toxicity (< grade 3 vs > or = grade 3). Of 344 patients, 81 (23.5%) were > 65 years old, 34 (9.9%) were > or = 70 years old, and 5 (1.5%) were > or = 75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged > or = 75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.

Adult↗
PubMed1984

Analysis of metastatic spread and growth of tumor cells in mice with depressed natural killer activity by anti-asialo GM1 antibody or anticancer agents.

The mechanism of artificial and spontaneous metastases of tumor was analyzed in B16 melanoma cells and C57BL/6 mice by using anti-asialo GM1 antibody and anticancer agents. Single administrations of 500 micrograms anti-asialo GM1 antibody resulted in significantly decreased NK activity in spleen cells of C57BL/6 mice, lasting 10 days from the day following administration. Treatment with anti-asialo GM1 antibody never decreased the function of T lymphocytes measured by blastogenesis with phytohemagglutinin or T cell growth factor. The tumoricidal functions of activated macrophages but not of resident macrophages were decreased by in vivo treatment with anti-asialo GM1 antibody. The anti-asialo GM1 antibody was evaluated in terms of the enhancing effect on pulmonary metastases with regard to the timing of administration. Treatment with anti-asialo GM1 antibody 1 day before or on the day of tumor inoculation resulted in a substantial increase in the number of artificial pulmonary metastases. In the experimental system of spontaneous metastases, anti-asialo GM1 antibody most effectively increased the number of pulmonary metastases when administered 1-2 weeks before the removal of primary tumor, when the tumor cells are thought to be released into blood circulation from the primary site. In addition, accelerated growth of transplanted tumors at the primary site was observed in mice treated with anti-asialo GM1 antibody. These results strongly suggest that anti-asialo GM1 antibody enhances the incidence of in vivo tumor metastases and the growth of transplanted tumor mainly by suppressing the function of NK cells. The maximum effective dose (MED) of mitomycin C or its derivative (M-83) suppressed NK activity significantly, and pretreatment with these anticancer agents enhanced the growth of the artificial pulmonary and liver metastases. In contrast, the MED of cDDP showed no effect on the NK activity or the numbers of pulmonary and liver metastases. These results indicate that the depression of NK activity induced by chemotherapy results in the promotion of metastatic disease. From these studies it can be concluded that NK cells have a key role in the control of metastases of malignant disease, and that support of NK activity is very important for the prevention of metastases.

Animals↗
PubMed1993

Metallothionein and anticancer agents: the role of metallothionein in cancer chemotherapy.

Metallothioneins (MTs) are intracellular proteins containing the highest amount of thiol groups within the cytoplasm. These thiol groups are able to bind several cytotoxic agents, such as platinum compounds and alkylating agents. Increased levels of MT are one mechanism of resistance to these anticancer drugs, as intracytoplasmic binding of MT prevents the active molecules from reaching their target, the intranuclear DNA of tumor cells. MT synthesis can easily be induced by physiologic heavy metals such as zinc and copper. Pharmacological modulation of MT levels has been used to increase the MT pool in normal tissues and decrease their susceptibility to the toxicity of anticancer drugs. In the case of tumors arising in the brain, where the inducibility of MT synthesis is low, this approach would allow protection of normal tissues without decreasing the antitumor activity of the cytotoxic agents. The interaction of MT with cytotoxic agents is not limited to covalent binding. A correlation between MT synthesis and amplification of oncogenes such as ras has been reported. Furthermore, the cytotoxic drugs are bound by MT after competition with zinc and copper; these metals are cofactors of numerous metalloenzymes, some of which are involved in the metabolism of nucleic acids. Competitive displacement of these metals might modify nucleic acid metabolism and influence cellular proliferation. On the other hand, increased MT levels could provide a zinc cofactor reserve that increases the cell's reparative potential when faced by DNA damage by cytotoxic agents.(ABSTRACT TRUNCATED AT 250 WORDS)

Alkylating Agents↗
PubMed1996

Current concepts of treatment in medical oncology: new anticancer drugs.

General principles for anticancer drug development include traditional drug-screening methods in biological test systems. Today, testing of a drug in a panel of selected human tumor xenografts in mice is assumed to have the best predictive value for clinical efficacy. Chemical modification of well-known antitumor drugs from compound groups such as purine analogs, vinca alkaloids, antifolates and platinum analogs are carried out to increase anticancer activity, to reduce toxic side-effects and to improve pharmacokinetic properties of the drugs. In the last decade the enormous development in molecular techniques has led to the discovery of key proteins that are intimately involved in the regulation of cancer growth control. Cell growth inhibitors could be developed by structure-based design, creating small organic molecules ("peptide mimetics") to target crucial enzymes, oncogenes or oncogene products, tumor-suppressor genes and their products as well as growth factors and their corresponding receptors. Drugs representing new leading structures, like alkylphosphocholines, topoisomerase I inhibitors, taxoids and suramin, have already entered the clinic. Novel therapeutic approaches may provide substantial progress in cancer treatment in the very near future. Examples are the concept of high-dose chemotherapy with hematopoietic stem cell support, the various strategies of gene therapy, the modulation of multi-drug resistance of cancer cells, and strategies to inhibit tumor angiogenesis.

Animals↗
PubMed1990

The pharmacokinetic model and distribution pattern of new sexual-steroid-hormone-linked anticancer agents.

Sexual-steroid-hormone-linked anticancer agents are a new group of cytotoxic drugs designed for a site-directed chemotherapy of tumors containing sexual steroid hormone receptors. The hormone (e.g. estradiol or testosterone) should act as a carrier that leads to a preferential receptor-mediated drug accumulation in hormone-receptor-positive tumors (such as mammary carcinomas and prostatic cancer). In several preclinical therapeutic studies of sexual-hormone-receptor-positive breast cancer, for instance, conjugates of 2-chloroethyl-carbamoyl-L-alanine linked to estradiol or dihydrotestosterone showed, in comparison to the unlinked single agent, a significantly higher antineoplastic activity and a clearly lower systemic toxicity. But there is still only limited knowledge about the pharmacokinetic properties and the mode of action of these new drugs. For this reason in the present article a more comprehensive pharmacokinetic model and the pattern of distribution of new sexual-steroid-hormone-linked anticancer agents have been described.

Antineoplastic Agents↗
PubMed1996

High-volume cellular screening for anticancer agents with combinatorial chemical libraries: a new methodology.

A single-step cancer cell cytotoxic assay system for anticancer drug discovery has been developed which facilitates rapid screening of large combinatorial chemical libraries synthesized using the 'one-bead-one-compound' (OBOC) methodology. Each OBOC library bead incorporates two orthogonally cleavable linkers that release the bead-bound compound at a different pH. The assay utilizes high concentrations of tumor cells mixed directly with OBOC beads and plated in soft agarose containing tissue culture medium. One of the orthogonal linkers is cleaved at neutral pH in tissue culture releasing an aliquot of compound to diffuse at a relatively high local concentration into the soft agarose immediately surrounding the bead. Active compounds are identified visually from a clear ring of tumor cell lysis which forms within 48 h around just the rare bead releasing a cytotoxic compound. The bead releasing a cytotoxin is then plucked from the agar and the remaining compound still linked to the bead can be released for structural analysis, followed by compound resynthesis and confirmatory testing. This assay system has been successfully applied to identification of lead cytotoxic compounds from model peptidic and non-peptidic combinatorial chemical libraries. Use of this methodology may facilitate anticancer drug discovery.

Animals↗
PubMed1981

Sensitivity of anticancer agents of human gastric cancers transplanted into nude mice.

In the chemotherapy for gastric cancer, the most sensitive anticancer agent against individual tumors should be prescribed. The establishment of a sensitivity test using nude mice as an in vivo model is urgently awaited by clinicians and researchers alike. Seventy-three tumors derived from human gastric cancer were transplanted subcutaneously into nude mice and these mice were then treated intraperitoneally with anticancer agents. Mitomycin C (MMC), 5-fluorouracil (5-FU) and cyclophosphamide (CPM) were used. The doses given were 3 mg/kg of MMC, 75 mg/kg of 5-FU and 200 mg/kg of CPM. IN 52 of the 73 cancers, chemosensitivity was evaluated by the microscopic changes in the tumors. The rate of positive sensitivity against gastric cancer was 42.2% in MMC, 34.6% in 5-FU and 30.8% in CPM, respectively. The sensitivity of each agent tested by this method indicated a good correlation with the clinical therapeutic effects. Our results suggest the feasibility of evaluation of the sensitivity of various agents from the microscopic changes on tumors transplanted into nude mice.

Animals↗
PubMed1983

In vitro soft agar assay by use of multiple for screening of tumor sensitivity to anticancer drugs.

For use in routine clinical studies, modifications in Hamburger's stem cell assay were made. A multiple with 24 wells made feasible, handling of a large number of samples. The addition of anticancer drugs to the bottom layer of agar led to avoidance of exposure to drugs before cell plating and evaluation of the effect of long-acting drugs such as 5-fluorouracil. Storage of the test plate including anticancer drugs in a freezer at -70 degrees C showed no loss of the colony forming activity. This method is simple, reliable and readily facilitated.

Agar↗
PubMed1986

A simple and rapid in vitro test for determining sensitivity of cancer cells to anticancer drugs.

For practical utilization of chemosensitivity tests of malignant cells to anticancer drugs in clinical studies, we developed a new method which is simple, rapid, and applicable to fresh human tumors. The principle of the method is to measure the content of ATP of living cells by chemoluminescence, after drug exposure. A straight linear relationship was observed between the number of viable cells and the light intensity. This method seems to be a good indicator for the selection of anticancer drugs in cancer chemotherapy.

Adenosine Triphosphate↗
PubMed1990

The effects of a single high voltage electrical stimulation with an anticancer drug on in vivo growing malignant tumors.

Giving a high voltage electrical stimulation (5 kv/cm, 2 msec) under bleomycin administration (5 mg/body, im) resulted in a significant size decrease of subcutaneously inoculated AH-109A hepatocellular carcinomas in Donryu rats. The tumor size decreased to an average 17 per cent of the initial mass 4 days after the treatment and the average survival period was extended to almost 200 per cent of that of the control. However, neither high voltage electrical stimulation nor bleomycin administration alone demonstrated an anticancer effect. It was thus concluded that the concomitant use of a high voltage electrical stimulation and an anticancer drug has the potential to be effectively applied in cancer treatment.

Animals↗
PubMed1999

P-glycoprotein-expressing tumor cells are resistant to anticancer drugs in human gastrointestinal cancer.

The resistance to doxorubicin (DOX) by some tumor cells is mainly due to the effect of P-glycoprotein encoded by the multidrug resistance-1 (mdr1) gene. We tried to prove the correlations between P-glycoprotein expression and the sensitivity for anticancer drugs including DOX and other cytotoxic drugs that are currently used for gastrointestinal cancer patients. We quantified the P-glycoprotein expression by flow cytometry techniques, and the sensitivity for anticancer drugs using a tetrazolium salt, 3-(4,5-di-methylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT), assay in highly purified fresh human tumor cells obtained from 25 cancer patients. The inhibition rates were the lowest in DOX and mitomycin C (MMC), compared with other drugs. The most significant correlation between DOX and MMC was seen in the inhibition rates. A significant correlation was also seen between the inhibition rates for DOX and P-glycoprotein expression, whereas only a slight correlation between the sensitivity for MMC and P-glycoprotein expression was observed. We should therefore pay close attention to the effect of P-glycoprotein when treating cancer patients, especially if both the inhibition rates of DOX and MMC are low based on the findings of an MTT assay.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMedDate not supplied

Transcatheter arterial chemoembolization with anticancer drug in iodized oil for primary hepatic carcinoma.

Transcatheter arterial chemoembolization using a suspension of anticancer drug in iodized oil combined with Gelfoam embolization was performed in 85 patients with advanced primary hepatic carcinoma. Long-term retention of iodized oil in the tumor was observed in 90% of the cases, and changes in tumor size were observable by abdominal X-ray film on follow-up studies. There was a decrease of tumor size in all cases and the overall 1-year survival rate was 43%. In tumors whose diameter was less than 20 cm and in patients without portal vein thrombosis the survival rate was nearly 60%. Combined treatment with anticancer drug in iodized oil and Gelfoam embolization of the proper hepatic artery was superior to use of the suspension alone. There was also better detection of small cancer nodules by the suspension as compared to conventional angiography.

Adult↗
PubMed1987

Induction of diffuse necrotizing enterocolitis by anticancer chemotherapy.

Fulminant, necrotizing colitis is a frequent, and generally fatal, complication of severe granulocytopenia, occurring during the treatment of hematological malignancies. In these cases, the patient complains of severe peritonitis, including nausea, vomiting, abdominal pain, diarrhea or melena, and a high temperature. Here, a rare case of anticancer chemotherapy-induced diffuse necrotizing enterocolitis throughout the entire intestinal tract is presented, which developed in a patient who did not have a hematologic malignancy but who had colon cancer, the only clinical symptom of which was watery stools, without any evidence of peritoneal irritation. Full attention should be paid to progressive diarrhea in patients with malignancies during anticancer chemotherapy.

Cisplatin↗
PubMed1984

Magnetic microcapsules for targeted delivery of anticancer drugs.

To achieve targeted distribution of anticancer drugs with sustained activity, ferromagnetic ethylcellulose microcapsules containing an anticancer drug, mitomycin C (FM-MMC-mc), were prepared by a method based on phase separation principles. Two prototypes of FM-MMC-mc were made: one with the drug as the core and zinc ferrite on its capsular surface (outer type); the other with both the drug and zinc ferrite as the core (inner type). Both preparations provided a sustained-release property and a sensitive response to conventional magnetic force, although certain differences in the release rate of drug, magnetic responsiveness, and particle size were found between the two dosage forms. Animal studies showed that the magnetic microcapsules could be magnetically controlled in the artery and urinary bladder. VX2 tumors in the rabbit hind limb and urinary bladder were successfully treated with magnetic control of FM-MMC-mc. Pharmacokinetic study revealed that the targeting of the microcapsules markedly enhanced the drug absorption into the surrounding tissues for a prolonged period of time. The results indicate the feasibility and effectiveness of the magnetic microcapsules as a targeted drug delivery system.

Animals↗
PubMed2006

Synthesis and in vitro evaluation of some novel benzofuran derivatives as potential anti-HIV-1, anticancer, and antimicrobial agents.

A novel series of 1-(1-benzofuran-2-yl-ethylidene)-4-substituted thiosemicarbazides (2a-d) along with some derived ring systems: substituted-2,3-dihydro-thiazoles (3a-c, 4a-f) and thiazolidin-4-ones (5a-d and 6a-d), were synthesized. In addition, cyanoacetic acid-(1-benzofuran-2-yl-ethylidene) hydrazide (7) was used to prepare another new series of compounds consisting of substituted pyridin-2(1H)-ones (8a-c); 2-thioxo-2,3-dihydro-thiazoles (9a-d) and 2-thioxo-2,3-dihydro-6H-thiazolo[4,5-d]pyrimidin-7-ones (10a-c, 11a-c). The absolute configuration of compound 5c was determined by X-ray crystallography. The compounds prepared were evaluated for their in vitro anti-HIV, anticancer, antibacterial, and antifungal activities. Among the tested compounds, compounds 5c and 9a produced a significant reduction [symbols, see text] the viral cytopathic effect (93.19% and 59.55%) at concentrations > 2.0 x 10(-4) M and 2.5 x 10(-5) M respectively. Compound 9a was confirmed to have moderate anti-HIV activity. Compounds 2a, 2d, and 5c showed mild antifungal activity. However, none of the tested compounds showed any significant anticancer activity.

Anti-HIV Agents↗
PubMed2000

Kinetics and mechanism for reduction of anticancer-active tetrachloroam(m)ine platinum(IV) compounds by glutathione.

Glutathione (GSH) reduction of the anticancer-active platinum(IV) compounds trans-[PtCl4(NH3)(thiazole)] (1), trans-[PtCl4(cha)(NH3)] (2), cis-[PtCl4(cha)(NH3)] (3) (cha=cyclohexylamine), and cis-[PtCl4(NH3)2] (4) has been investigated at 25 degrees C in a 1.0 M aqueous medium at pH 2.0-5.0 (1) and 4.5-6.8 (2-4) using stopped-flow spectrophotometry. The redox reactions follow the second-order rate law d[Pt(IV)]/dt=k[GSH]tot[Pt(IV)], where k is a pH-dependent rate constant and [GSH]tot the total concentration of glutathione. The reduction takes place via parallel reactions between the platinum(IV) complexes and the various protolytic species of glutathione. The pH dependence of the redox kinetics is ascribed to displacement of these protolytic equilibria. The thiolate species GS is the major reductant under the reaction conditions used. The second-order rate constants for reduction of compounds 1-4 by GS- are (1.43 +/- 0.01) x 10(7), (3.86 +/- 0.03) x 10(6), (1.83 +/- 0.01) x 10(6), and (1.18 +/- 0.01) x 10(6) M(-1)s(-1), respectively. Rate constants for reduction of 1 by the protonated species GSH are more than five orders of magnitude smaller. The mechanism for the reductive elimination reactions of the Pt(IV) compounds is proposed to involve an attack by glutathione on one of the mutually trans coordinated chloride ligands, leading to two-electron transfer via a chloride-bridged activated complex. The kinetics results together with literature data indicate that platinum(IV) complexes with a trans Cl-Pt-Cl axis are reduced rapidly by glutathione as well as by ascorbate. In agreement with this observation, cytotoxicity profiles for such complexes are very similar to those for the corresponding platinum(II) product complexes. The rapid reduction within 1 s of the platinum(IV) compounds with a trans Cl-Pt-C1 axis to their platinum(II) analogs does not seem to support the strategy of using kinetic inertness as a parameter to increase anticancer activity, at least for this class of compounds.

Antineoplastic Agents↗