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PubMed1996

Chromosomal changes in rheumatoid arthritis patients treated with CPH82.

Chromosomal changes were assessed in 19 patients with rheumatoid arthritis (RA) treated with CPH82, a benzylidated podophyllotoxin glycoside, for up to one year. The frequency of chromosomal aberrations (CA) and sister chromatid exchanges (SCE) in peripheral lymphocytes increased significantly after 12 weeks of treatment and remained elevated after 48 weeks treatment in peripheral lymphocytes. The number of CA and SCE were significantly increased in CPH82 treated patients compared with the RA patients treated with other disease modifying anti-rheumatic drug (sulphasalazine, gold, D-penicillamine, azathioprine, methotrexate, cyclophosphamide). Only two patients treated with cyclophosphamide and azathioprine had changes of comparable levels. The results of this study suggest a mutagenic potential of CPH82 similar to that described for other immunosuppressive drugs and the newer podophyllotoxin derivatives, etoposide and teniposide.

Anti-Inflammatory Agents, Non-Steroidal↗

PubMed1990

Characterization of an etoposide-resistant human small-cell lung cancer cell line.

We established an etoposide (VP-16)-resistant human small-cell lung cancer cell line (H69/VP) by stepwise exposure to VP-16. The resistance of H69/VP to VP-16 was 9.4-fold that of the parent cell line (H69/P). H69/VP showed cross-resistance to Adriamycin (ADM), (4S)-4,11-diethyl-4-hydroxy-9-[(4-piperidinopiperidino) carbonyloxy]-1H-pyrano[3',4':6,7]indolizino [1,2-b]quinoline-3,14(4H,12H)-dionehydrochloride trihydrate (CPT-11), teniposide (VM-26), vindesine (VDS) and vincristine (VCR). The amount of DNA topoisomerase II (topo.II) was nearly the same in H69/P and H69/VP cells. The catalytic activity of topo.II in H69/VP cells was lower than that in the H69/P line. Accumulation of [3H]-VP-16 in H69/VP was 6.1-7.5 times lower than that in H69/P. According to Northern blot analysis, the mdr-1 mRNA level in H69/VP was markedly higher than that in H69/P. These findings suggest that H69/VP has a typical multidrug resistance (MDR) phenotype and that alteration of the drug accumulation mediated by P-glycoprotein may play an important role in resistance to VP-16. Reduced topo.II activity may also be associated with VP-16 resistance.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed2004

Biotechnological aspects of the production of the anticancer drug podophyllotoxin.

The natural lignan podophyllotoxin, a dimerized product of two phenylpropanoid moieties which occurs in a few plant species, is a pharmacologically important compound for its anticancer activities. It is used as a precursor for the chemical synthesis of the anticancer drugs etoposide, teniposide and etopophose. The availability of this lignan is becoming increasingly limited because of the scarce occurrence of its natural sources and also because synthetic approaches for its production are still commercially unacceptable. Biotechnological production using cell culture may be considered as an alternative source. Selection of the best performing cell line, its maintenance and stabilization are necessary prerequisites for its production in bioreactors and subsequent scale-up of the cultivation process to the industrial level. Scale-up of growth and product yield depends on a multitude of factors, such as growth medium, physicochemical conditions, seed inoculum, type of reactor and processing conditions. The composition of the growth medium, elicitors and precursors, etc. can markedly influence the production. Optimum levels of parameters that facilitate high growth and product response in cell suspensions of Podophyllum hexandrum have already been determined by statistical design. P. hexandrum cells have successfully been cultivated in a 3-l stirred-tank bioreactor under low shear conditions in batch and fed-batch modes of operation. The batch kinetic data were used to identify the mathematical model which was then used to develop nutrient-feeding strategies for fed-batch cultivation to prolong the productive log phase of cultivation. An improvement in the production of podophyllotoxin to 48.8 mg l(-1) in a cell culture of P. hexandrum was achieved, with a corresponding volumetric productivity of 0.80 mg l(-1) day(-1), when the reactor was operated in continuous cell-retention mode. Efforts are being made to further enhance its production levels by the development of hairy root culture or by varying the channeling of precursors towards the desired biosynthetic pathway by molecular approaches.

Antineoplastic Agents, Phytogenic↗

PubMed1996

High-dose therapy followed by bone marrow transplantation for relapsed follicular non-Hodgkin's lymphoma. Dutch HOVON Group.

PURPOSE: To analyze whether, in addition to survival, and disease-free survival progression-free interval after transplantation would be longer than the last progression-free interval before transplantation, supporting the argument that high-dose therapy may change the biologic behavior of the disease. PATIENTS AND METHODS: Patients with a poor-risk relapsed follicular NHL were treated with three cycles of doxorubicin 50 mg/m2 and teniposide 60 mg/m2, followed by etoposide 350 mg/m2, cyclophosphamide 60 mg/kg, and TBI and unpurged BMT. RESULTS: Twelve patients were entered in the study. Ten patients fulfilled the criteria for response and underwent transplantation, two of them with an allograft. Nine of ten patients with transplants achieved a complete remission after BMT. One patient died on day 41 due to veno-occlusive disease. The nine patients with transplants who were evaluable for follow-up had a conversion of remission or response duration after transplantation, their progression-free interval after BMT being superior to the last one before BMT with a median of 1044 + days. Overall survival and disease-free survival in the transplant patients after a median follow-up of 1160 days from BMT is 90%. CONCLUSION: High dose chemotherapy followed by stem cell rescue may change the clinical course in follicular non-Hodgkin's lymphoma patients.

Adult↗

PubMed2006

Single nucleotide polymorphisms and expression of ERCC1 and ERCC2 vis-à-vis chemotherapy drug cytotoxicity in human glioma.

ERCC1 and ERCC2 have been known to belong to the nucleotide excision repair (NER) pathway and are essential to the repair of cisplatin DNA adducts. In the present study, we have examined the potential correlation of ERCC1, ERCC2 mRNA expression and single nucleotide polymorphism (SNP) to chemotherapy drug cytotoxicity from 49 human gliomas. Fresh human glioma specimens were obtained during surgery. SNPs of ERCC1 and ERCC2 was determined by single strand conformation polymorphism (SSCP) and sequencing. ERCC1 and ERCC2 expression was quantified using real-time quantitative reverse transcription-PCR. Chemotherapy drug cytotoxicity was determined by the tetrazolium (MTT) assay for cisplatin (CDDP), 1,3-bis-(2-chloroethyl)-1-nitrosourea (BCNU), vincristine (VCR) and teniposide (VM26). The results show that there was no statistically significant association between the C8092A polymorphism of ERCC1 or codon 312 and codon 751 polymorphisms of ERCC2 and the chemotherapy drug cytotoxicity. However there was a strong correlation between ERCC1 and ERCC2 mRNA expression levels (Spearman r = 0.42; P < 0.003). Further more, tumor samples with low ERCC1 mRNA expression levels showed enhanced CDDP cytotoxicity (P = 0.0001) while ERCC2 expression was reversely correlated with BCNU cytotoxicity (P = 0.004). In sum, Our results indicated that ERCC1 mRNA expression is associated with CDDP cytotoxicity and ERCC2 mRNA levels is related with BCNU cytotoxicity, while there was no correlation between SNP of ERCC1, ERCC2 and in vitro cytotoxicity of four anticancer drugs, CDDP, BCNU, VCR and VM26.

Adolescent↗

PubMed1985

Inhibition of epipodophyllotoxin cytotoxicity by interference with topoisomerase-mediated DNA cleavage.

This laboratory and others previously proposed that the antitumor effects of the epipodophyllotoxin compounds are based on their abilities to stimulate DNA cleavage by a DNA topoisomerase. To explore this relationship further, we studied the intercalating agent ethidium bromide and found that it blocked epipodophyllotoxin-induced DNA cleavage by DNA topoisomerase II in vitro as well as in vivo. Using an in vitro assay consisting of purified calf thymus DNA topoisomerase II, end-labeled DNA, and the epipodophyllotoxin teniposide, we found that ethidium bromide markedly interfered with the enzyme-mediated DNA cleavage. Furthermore, ethidium bromide also blocked the formation of DNA single- and double-strand breaks in mouse L1210 cells when exposed to the epipodophyllotoxin etoposide. This effect cannot be explained by alterations in drug accumulation since steady-state drug concentrations were unchanged, and the effect was also observed in isolated nuclei. In addition to its effects on epipodophyllotoxin-mediated DNA breakage, ethidium bromide also potently inhibited the cytotoxic effects of etoposide but only when present during drug treatment. Thus, we believe that ethidium bromide may be a useful tool to investigate drug-induced perturbations of topoisomerase activity and their relationship to antitumor effect. Our data strongly support the hypothesis that the antitumor activity of epipodophyllotoxins is based on the ability to stimulate the formation of a cleavable complex between DNA topoisomerase and DNA.

Animals↗

PubMed1986

Chloroquine enhancement of anticancer drug cytotoxicity in multiple drug resistant human leukemic cells.

Vinblastine-sensitive (CCRF-CEM) and -resistant (CEM/VLB100) human T-cell lymphoblasts were treated with the lysosomotropic agent chloroquine. As measured by growth inhibition, this drug enhanced the cytotoxicity of vinblastine in the CEM/VLB100 cells but was less effective in the CCRF-CEM cells. Chloroquine also enhanced the cytotoxic activity of vincristine, daunorubicin and doxorubicin and, to a lesser extent, teniposide (VM-26) in the CEM/VLB100 cells. Histological examination revealed that the vinblastine-resistant cells contained more cytoplasmic vacuoles than their drug-sensitive counter-parts. When the CEM/VLB100 cells were treated with chloroquine, vinblatine, or a combination of the two, the cells displayed many more cytoplasmic vacuoles than the controls. Coincident with the increased number of vacuoles, these treated cells stained more intensely than controls for the lysosomal enzyme, acid phosphatase, but not for lipid. The vacuolization did not increase as much in the CCRF-CEM cell line when these cells were exposed to the chloroquine + vinblastine combination. Vacuolization was also associated with vincristine, doxorubicin, and daunorubicin treatments, but not with VM-26. We conclude that chloroquine is a modulator of anticancer drug action in the CEM/VLB100 cell line.

Antibiotics, Antineoplastic↗

PubMed1992

Chromosomal changes in Chinese hamster AA8 cells caused by podophyllin, a common treatment for genital warts.

Podophyllin, a plant derivative of variable composition, is used widely within New Zealand as a treatment for genital warts. One local source of podophyllin has been tested for ability to cause mutagenic effects in Salmonella typhimurium as well as for effects on chromosomes of Chinese hamster AA8 cells. Although only weakly mutagenic in one strain of Salmonella, podophyllin caused structural aberrations as well as changes in chromosome number in the Chinese hamster cells. The range of aberrations was similar to those caused by teniposide, a close structural relative of the major component, which was used as a positive control in the Chinese hamster cell experiments. A literature review revealed that podophyllin was shown to cause changes of chromosome number in the mouse cervix in vivo, although aberrations were not studied. Patients treated with podophyllin will usually possess one form of the papilloma virus, and this itself may have some oncogenic potential. We suggest that podophyllin could potentiate these effects and question its continued widespread use.

Animals↗

PubMed1994

International Commission for Protection Against Environmental Mutagens and Carcinogens. Mutagenicity and carcinogenicity of topoisomerase-interactive agents.

Drugs that interact with DNA topoisomerases I and II hold great promise for the treatment of cancer, however, like many other anti-cancer agents, they are a double-edged sword and may themselves cause mutation and cancer. In vitro studies show that clinically effective agents, such as etoposide, doxorubicin and others, stabilize a ternary complex where topoisomerase II is covalently linked to DNA. This complex represents an intermediate in the topoisomerase-II catalyzed DNA supercoil relaxation reaction. Camptothecin and its analogues stabilize a similar ternary complex, in vitro, consisting of topoisomerase I covalently linked to DNA at single-strand breaks. Short-term tests of genotoxicity confirm that topoisomerase-interactive agents are mutagenic and suggest common mechanisms by which they induce mutation and selectively kill tumor cells. These agents induce sister-chromatid exchange, chromosomal aberrations and mutations in specific mammalian genes. Their propensity to induce small colonies in the L5178/TK+/(-)-3.7.2C assay implies that topoisomerase-interactive agents induce large DNA rearrangements and deletions. These may result from topoisomerase-subunit exchange at drug-stabilized ternary complexes or from attempts by the cell to bypass the replication block caused by stabilized ternary complexes. Studies in bacterial mutation assays suggest that topoisomerase-interactive agents may also induce mutations, albeit at a lower rate, through simple DNA intercalation or via generation of oxygen free radicals. Second malignancies observed in patients previously treated with topoisomerase II interactive agents suggest these may be an important clinical consequence of their capacity to induce mutation. In particular, a unique form of acute myelogenous leukemia is observed at strikingly high frequencies after treatment with relatively high doses of the epipodophyllotoxins etoposide and teniposide. This form of AML has been reported after the uses of other classes of topoisomerase-interactive agents as well. Cancer induction is therefore a toxic consequence predicted by short-term tests of genotoxicity and should be weighed against the potential therapeutic benefits of topoisomerase-interactive agents.

Animals↗

PubMed1991

Improved outcome in childhood acute lymphoblastic leukaemia with reinforced early treatment and rotational combination chemotherapy.

To improve outcome in childhood acute lymphoblastic leukaemia (ALL), a stratified, randomised study of extended intensified chemotherapy was done. 358 evaluable patients received remission reinforcement therapy (teniposide, cytarabine, high-dose methotrexate) added to a four-drug induction regimen. Those achieving complete remission were randomised on the basis of risk group assignment to conventional continuation treatment or to four pairs of drugs rotated weekly or every 6 weeks. All patients received intrathecal chemotherapy; higher-risk patients also received 1800 cGy cranial irradiation after 1 year of remission. Complete remission was induced in 96% of the patients. At median follow-up of 40 (range 19-73) months, 4-year event-free survival (SE) was 73 (4)% overall, 81 (6)% in the lower-risk group (n = 110), and 69 (5)% in the higher-risk group (n = 248). Outcome within risk groups was not significantly affected by the speed of rotation of drug pairs during continuation treatment. Various high-risk subgroups had apparently improved responses to this treatment. This intensified chemotherapy may cure 69-77% of children with ALL.

Actuarial Analysis↗

PubMed1992

Radiotherapy- and chemotherapy-induced myelodysplasia and acute myeloid leukemia. A review.

A highly increased risk of myelodysplasia (MDS) and acute myeloid leukemia (AML) has been demonstrated following therapy with alkylating agents. The risk increases with cumulative dose and with the age of the patient. Most cases of MDS and AML following therapy with alkylating agents present chromosome aberrations, primarily loss of whole chromosomes No. 5 and/or No. 7 or various parts of the long arms of these chromosomes. The risk of MDS and AML following high-voltage radiotherapy is much lower. Recently an increased risk of AML has been demonstrated following therapy with the epipodophyllotoxins etoposide and teniposide. These leukemias typically present without preceding MDS and often show balanced aberrations of chromosome bands 11q23 and 21q22.

Acute Disease↗

PubMed1990

Inhibition of DNA synthesis and cytotoxic effects of some DNA topoisomerase II and gyrase inhibitors in Chinese hamster V79 cells.

In this study, some DNA topoisomerase II and gyrase inhibitors have been identified as inhibitors of polymerization of deoxyribonucleotides [novobiocin (NVB), nalidixic acid (NDA), oxolinic acid (OXA)], or inhibitors of replicon initiation and DNA-chain elongation [etoposide (VP-16), teniposide (VM-26), 4'-(9-acridinylamino)methansulfon-m-anisidine (m-AMSA), ellipticine (ELT)]. The inhibitors of deoxyribonucleotide polymerization produced a significant (greater than 85%) suppression of [3H]thymidine incorporation into V79 cells within 20 min of treatment, followed by a rapid recovery of DNA synthesis, and reduced cell killing. In contrast, the inhibitors of replicon initiation and DNA-chain elongation needed about 60 min to induce a partial, but irreversible inhibition of DNA replication, associated with extensive cell killing.

Animals↗

PubMed1990

Basement membrane collagen-degrading activity from a malignant tumor is inhibited by anthracycline antibiotics.

Type IV collagenase activity was previously identified and purified to 7500-fold in homogenates from murine Walker 256 carcinoma, using acetylated [3H]-type IV collagen as a substrate. Anthracycline antibiotics daunorubicin, doxorubicin and epirubicin exhibited a non-competitive, reversible inhibition with Ki 92, 49 and 40 microM, respectively. This inhibitory effect, at therapeutically attainable concentrations of the forementioned antineoplastic drugs, may contribute, at least in part, to their antimetastatic properties. The anthracycline derivatives: 4-demethoxydaunorubicin, 4'-iododoxorubicin and 4-demethoxy-3'-deamino-3'-hydroxyepirubicin were without inhibitory effects at comparable concentrations. Other antineoplastic agents, such as belomycin, carmustine, cisplatine, etoposide, methotrexate, mitotane and teniposide did not exhibit any inhibitory effect at concentrations up to 1.0 mM.

Animals↗

PubMed1990

Modulation of cytotoxicity of cytostatic drugs by hemodialysis in vitro and in vivo.

For most cytotoxic substances there are no established guidelines on how to deal with overdosage. Little is known about the dialysability of cytostatic drugs. To obtain further information, human plasma was incubated with cytostatic drugs and dialysed in vitro, using 'minimodules' with capillaries identical to those in clinical use. Cytotoxicity before and after dialysis was measured in a biological test system using permanent human lymphoblast cultures (LS2). The 20 cytostatic drugs studied were categorized as follows: (1) Dialysability in vitro. Good: methotrexate (MTX), 5-fluorouracil (5-FU/5-FUdR), cytarabine (ARAC), actinomycin D (DACT), mitomycin C (MMC), 4-OH-cyclophosphamide (4-OH-CPM), ifosfamide (IFO), melphalan (L-PAM), dacarbazine (DTIC), cisplatin (DDP). Intermediate: Adriamycin (ADM), 4'-epi-doxorubicin (4'-EA), carmustine (BCNU). Ineffective: daunorubicin (DNR), vincristine (VCR), vinblastine (VBL), vindesine (VDS), etoposide (VP-16), teniposide (VM-26), mitoxantrone (MITOX). These in vitro results cannot be transferred automatically into the in vivo situation because of specific drug distribution and metabolic rates. Considering pharmacokinetic data from the literature, the following recommendations can be made for practical clinical purposes. (2) Detoxification by hemodialysis in vivo. Possibly effective: MTX, 5-FU, MMC, CPM, IFO, L-PAM, BCNU, DTIC. Ineffective: ADM, 4'-EA, DNR, MITOX, DACT, VP-16, VM-26, VCR, VBL, VDS, ARAC, DDP.

Antineoplastic Agents↗

PubMed1989

High dose chemotherapy including vepeside, cyclophosphamide and carboplatin with autologous bone marrow transplantation in one case of chemoresistant testicular cancer.

Non seminomatous germ cell testicular tumors (NSGCTT) is a very chemosensitive cancer; vepeside, cyclophosphamide or ifosfamide and cisplatin are the most effective drugs. Carboplatin is also active with a lack of nephrotoxicity, but there is probably a cross-resistance to cisplatin. High dose chemotherapy with autologous bone marrow transplantation is able to cure poor prognosis testicular cancers in first partial remission or in sensitive relapse. We report one case of non seminomatous testicular cancer which was progressive after chemotherapy with cisplatin and vepeside or teniposide, and which is in prolonged complete remission after conventional chemotherapy (vepeside, ifosfamide, carboplatin) and high dose chemotherapy (carboplatin, vepeside, cyclophosphamide) with autologous bone marrow transplantation.

Adult↗

PubMed1993

Biochemical characterisation of elsamicin and other coumarin-related antitumour agents as potent inhibitors of human topoisomerase II.

Elsamicin (EM) is a recently discovered antitumour agent that is structurally related to several other compounds displaying anticancer activities, including chartreusin (CT), chrysomycin V (CV) and M (CM), gilvocarcin V (GV) and ravidomycin (RM). The biochemical events resulting in cytotoxicity for most of these compounds have not been clearly elucidated. There is some evidence that GV and CT bind to DNA and that GV is photosensitive, causing DNA damage. Therefore, we investigated the effects of these chemicals on DNA in cells and on pBR322 plasmid DNA. Using alkaline elution techniques, we found that all these compounds induced, to a different extent, DNA breakage in the human lung adenocarcinoma A549 cell line. In addition, all either bound to or intercalated into DNA, as indicated by their ability to alter the electrophoretic migration of DNA in agarose gels. Using the P4 unknotting assay, EM, CT, CV, CM, GV and RM were found to be potent inhibitors of the catalytic activity of topoisomerase II (topo II). Their potencies were compared with the known topo II inhibitors teniposide (VM-26) and doxorubicin (DX). EM was the most potent, with an IC50 of 0.4 mumol/l followed in order by CV, GV, and CT. VM-26 was the least potent with an IC50 of 15 mumol/l. It was concluded from these results that EM, GV, CV, CM and CT are capable of inhibiting topo II and that EM is the most potent inhibitor of topo II yet discovered.

Adenocarcinoma↗

PubMed1995

The treatment of advanced neuroblastoma. Results of the Spanish Neuroblastoma Study Group (SNSG) studies.

The Spanish Neuroblastoma Study Group has conducted a study on advanced neuroblastoma (N-I-87), which included 33 stage III and 60 stage IV neuroblastoma children more than 1 year of age, enrolled between October 1987 and April 1992. They were staged according to Evans and treated with induction chemotherapy (IC) consisting of 3 courses of cyclophosphamide-doxorubicin alternating with 3 of high-dose cisplatin-teniposide. Evaluation after IC and surgery demonstrated an overall response rate of 88% for stage III and 69% for stage IV. In the latter, complete responses and good partial responses were 33 and 14%, respectively. After surgery, children received maintenance chemotherapy (all stage III except 2 and 30 stage IV) or autologous bone marrow transplantation (ABMT) (11 stage IV), the distribution was not randomised. Probability of survival at 5 years was 0.60 +/- 0.12 for stage III and 0.24 +/- 0.07 for stage IV. A significant difference in survival at 5 years was found between "good responders" and "non-responders" to initial chemotherapy.

Adolescent↗

PubMed2005

Plant-based anticancer molecules: a chemical and biological profile of some important leads.

A number of natural products, with diverse chemical structures, have been isolated as anticancer agents. Several potential lead molecules such as camptothecin, vincristine, vinblastine, taxol, podophyllotoxin, combretastatins, etc. have been isolated from plants and many of them have been modified to yield better analogues for activity, toxicity or solubility. Several successful molecules like topotecan, irinotecan, taxotere, etoposide, teniposide, etc. also have emerged as drugs upon modification of these natural leads and many more are yet to come. In this review, the authors have focused on four important anticancer leads, that is, camptothecin, taxol, combretastatin A-4 and podophyllotoxin. Their chemistry, structure and activity relationships, biological activities, modes of action, analogue synthesis and future prospects have been discussed.

Animals↗