Inherited susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes.
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BACKGROUND: Susceptibility to bleomycin-induced chromatid breaks in cultured peripheral blood lymphocytes may reflect the way a person deals with carcinogenic challenges. This susceptibility (also referred to as mutagen sensitivity) has been found to be increased in patients with environmentally related cancers, including cancers of the head and neck, lung, and colon, and, in combination with carcinogenic exposure, this susceptibility can greatly influence cancer risk. The purpose of this study was to assess the heritability of mutagen sensitivity. METHODS: Heritability was determined by use of a maximum likelihood method that employed the FISHER package of pedigree analysis. Bleomycin-induced breaks per cell values for 135 healthy volunteers without cancer were determined. These individuals were from 53 different pedigrees and included 25 monozygotic twin pairs (n = 50), 14 pairs of dizygotes (twin pairs and siblings, n = 28), and 14 families selected on the basis of a first-degree relative who was successfully treated for head and neck cancer and who had no sign of recurrence for at least 1 year. All data were analyzed simultaneously, and different models of familial resemblance were fitted to the data. All P values are two-sided. RESULTS: Our results showed no evidence for the influence of a shared family environment on bleomycin-induced chromatid breaks. Genetic influences, however, were statistically significant (P =. 036) and accounted for 75% of the total variance. CONCLUSIONS: The high heritability estimate of the susceptibility to bleomycin-induced chromatid breaks indicates a clear genetic basis. The findings of this study support the notion that a common genetic susceptibility to DNA damage--and thereby a susceptibility to cancer--may exist in the general population. (+info)
125I-labelled human chorionic gonadotrophin (hCG) as an elimination marker in the evaluation of hCG decline during chemotherapy in patients with testicular cancer.
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The rate of reduction in the concentration of serum human chorionic gonadotrophin (hCG) following chemotherapy for germ cell tumours may follow a complex pattern, with longer apparent half-life during later stages of chemotherapy, even in patients treated successfully. The commonly used half-life of less than 3 days for hCG to monitor the effect of chemotherapy in patients with germ cell tumours of the testis may represent too simple a model. 125I-labelled hCG was injected intravenously in 27 patients with germ cell tumours and elevated hCG during chemotherapy. The plasma radioactivity and hCG concentrations were followed. During chemotherapy, the plasma disappearance of hCG showed a biphasic pattern, with an initial fast and a later slow component in all patients. Using the steep part of the hCG plasma disappearance curve, five patients who achieved long-term remission had half-lives longer than 3 days (3.6-6.8 days), whereas four out of five patients not achieving long-term remission had half-lives shorter than 3 days. After the third treatment cycle, eight patients who achieved long-term remission had hCG half-lives longer than 3 days (7.4-17.0 days). In these patients, the plasma disappearance of [125I]hCG was equivalent to that of hCG. Thus, the slow decline of hCG represented a slow plasma disappearance rather than a hCG production from vital tumour cells and could, consequently, not be used to select patients for additional or intensified chemotherapy. The concept of a fixed half-life for plasma hCG during treatment of hCG-producing germ cell tumours is inappropriate and should be revised. Difficulties in interpreting a slow decline of hCG may be overcome by comparing the plasma disappearance of total hCG with the plasma disappearance of [125I]hCG. (+info)
Identification and characterization of a type II peptidyl carrier protein from the bleomycin producer Streptomyces verticillus ATCC 15003.
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BACKGROUND: Nonribosomal peptide synthetases (NRPSs) catalyze the assembly of a structurally diverse group of peptides by the multiple-carrier thiotemplate mechanism. All NRPSs known to date are exclusively type I modular enzymes that consist of domains, such as adenylation (A), peptidyl carrier protein (PCP) and condensation (C) domains, for individual enzyme activities. Although several A and PCP domains have been demonstrated to function independently, aminoacylation in trans has been successful only between PCPs and their cognate A domains. RESULTS: We have identified within the bleomycin-biosynthesis gene cluster from Streptomyces verticillus ATCC15003 the blmI gene that encodes a discrete PCP protein. We overexpressed the blmI gene in Escherichia coli, purified the BlmI protein, and demonstrated that apo-BlmI can be efficiently modified into holo-BlmI either in vivo or in vitro by PCP-specific 4'-phosphopantetheine transferases (PPTases). Unlike the PCP domains in type I NRPSs, BlmI lacks its cognate A domain and can be aminoacylated by Val-A, an A domain from a completely unrelated type I NRPS. CONCLUSIONS: BlmI represents the first characterized type II PCP. The BlmI type II PCP, like the PCP domains of type I NRPSs, can be 4'-phospho-pantetheinylated by PCP-specific PPTases but is biochemically distinct in that it can be aminoacylated by an A domain from a completely unrelated type I NRPS. Our results provide for the first time the genetic and biochemical evidence to support the existence of a type II NRPS, which might be useful in the combinatorial manipulation of NRPS proteins to generate novel peptides. (+info)
Sixty percent salvage rate for germ-cell tumours using sequential m-BOP, surgery and ifosfamide-based chemotherapy.
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BACKGROUND: In germ-cell tumours (GCT), there is continuing controversy over the relative merits of dose dense therapy (increased frequency over a given time) versus vertical intensification (increased dose per fraction). The value of using a cisplatin-based dose dense approach in the salvage setting has not been documented and in addition the role of methotrexate remains uncertain. This paper reviews results from our investigations of these issues. PATIENTS AND METHODS: Between 1987 and 1996, 65 patients with relapsing or refractory germ-cell tumour received weekly m-BOP (methotrexate, bleomycin, vincristine and cisplatin) as salvage therapy. Residual masses were excised if possible and patients progressing after this received cisplatin and ifosfamide based chemotheraphy with or without high dose chemotherapy (HDCT) consolidation. RESULTS: With a median follow-up of 33 months, 34% are progression free following m-BOP, 11% who had surgery for residual masses which showed viable cancers are progression free. A further 15% who progressed following m-BOP with or without surgery were rendered progression free by third-line therapy. CONCLUSIONS: The use of m-BOP as second line therapy with deferment of cisplatin and ifosfamide based treatment to third line therapy with consolidation of third line responses with HDCT, leads to an overall progression-free survival of 60%. It does not appear that M-BOP prejudiced the response to third line therapy suggesting a lack of cross resistance. The potentially lower risk of leukaemia and infertility from m-BOP requires further evaluation. (+info)
The role of chemotherapy in intracranial germinoma: a case report.
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BACKGROUND: The case of a 29-year-old man with histologically proven simultaneous germinoma (seminoma) of the pineal gland and a stage I embryonal carcinoma of the testis is reported. An intradural metastatic lesion from the pineal germinoma was diagnosed at the level of the first thoracic vertebra. Treatment, after inguinal orchiectomy, was chemotherapy only, rather than conventional radiotherapy for the pineal germinoma. METHODS: Therapy consisted of bleomycin (B), etoposide (E) and cisplatin (P). MRI was used to assess the effectiveness of BEP chemotherapy. RESULTS: A complete remission of the pineal gland germinoma and the epidural metastasis was documented after two cycles of BEP chemotherapy and after 15 months of follow-up the patient remains free of relapse. DISCUSSION: The pathogenesis of simultaneously occurring germinoma of the pineal gland and embryonal cell carcinoma of the testis is discussed. The choice of therapy in these circumstances is a matter of debate and the good result of chemotherapy alone in this patient suggest that primary chemotherapy may be the therapy of choice in patients with pineal germinomas. (+info)
DNA damage increases sensitivity to vinca alkaloids and decreases sensitivity to taxanes through p53-dependent repression of microtubule-associated protein 4.
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Taxanes and Vinca alkaloids are among the most active classes of drugs in the treatment of cancer. Yet, fewer than 50% of previously untreated patients respond, and clinicians have few ways of predicting who will benefit from treatment and who will not. Mutations in p53 occur in more than half of human malignancies and may alter the sensitivity to a variety of anticancer therapies. We have shown that the transcriptional status of p53 determines the sensitivity to antimicrotubule drugs and that this is mediated through the regulation of microtubule-associated protein 4 (MAP4). Expression of MAP4 is transcriptionally repressed by wild-type p53. Increased expression of MAP4, which occurs when p53 is transcriptionally inactive, increases microtubule polymerization, paclitaxel binding, and sensitivity to paclitaxel, a drug that stabilizes polymerized microtubules. In contrast, overexpression of MAP4 decreases microtubule binding and sensitivity to Vinca alkaloids, which promotes microtubule depolymerization. To determine whether induction of endogenous wild-type p53 by DNA-damaging agents alters the expression of MAP4 and changes the sensitivity to antimicrotubule drugs, we assayed cell lines with wild-type or mutant p53 for the expression of MAP4 and drug sensitivity before and after DNA damage. UV irradiation, bleomycin, and doxorubicin increased wild-type p53 expression and decreased MAP4 expression. These changes were associated with decreased sensitivity to paclitaxel and increased sensitivity to vinblastine. These changes in drug sensitivity were no longer observed when p53 and MAP4 returned to baseline levels. Changes in drug sensitivity following DNA-damaging agents were associated with decreased binding of paclitaxel and increased binding of Vinca alkaloids. In contrast, DNA damage did not alter the sensitivity to non-microtubule-active drugs, such as 1-beta-D-arabinofuranosylcytosine and doxorubicin. Changes in drug sensitivity following DNA-damaging drugs were not observed in cells with mutant p53. These studies demonstrate that induction of wild-type p53 by DNA-damaging agents can affect the sensitivity to antimicrotubule drugs through the regulation of MAP4 expression and may have implications for the design of clinical anticancer therapies. (+info)
Repair of apurinic/apyrimidinic sites by UV damage endonuclease; a repair protein for UV and oxidative damage.
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UV damage endonuclease (UVDE) initiates a novel form of excision repair by introducing a nick imme-diately 5" to UV-induced cyclobutane pyrimidine dimers or 6-4 photoproducts. Here, we report that apurinic/apyrimidinic (AP) sites are also nicked by Neurospora crassa and Schizosaccharomyces pombe UVDE. UVDE introduces a nick immediately 5" to the AP site leaving a 3"-OH and a 5"-phosphate AP. Apyrimidinic sites are more effectively nicked by UVDE than apurinic sites. UVDE also possesses 3"-repair activities for AP sites nicked by AP lyase and for 3"-phosphoglycolate produced by bleomycin. The Uvde gene introduced into Escherichia coli cells lacking two types of AP endonuclease, Exo III and Endo IV, gave the host cells resistance to methylmethane sulfonate and t-butyl hydroperoxide. We identified two AP endonuclease activities in S.pombe cell extracts. Besides cyclobutane pyrimidine dimers and 6-4 photoproducts, N. crassa UVDE also nicks Dewar photoproducts. Thus, UVDE is able to repair both of the major forms of DNA damage in living organisms: UV-induced DNA lesions and AP sites. (+info)
Reduction of bleomycin induced lung fibrosis by transforming growth factor beta soluble receptor in hamsters.
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BACKGROUND: Transforming growth factor beta (TGF-beta) is a key mediator of collagen synthesis in the development of lung fibrosis. It has previously been shown that the administration of TGF-beta antibody and TGF-beta binding proteoglycan, decorin, reduced bleomycin (BL) induced lung fibrosis in animals. The present study was carried out to investigate whether intratracheal instillation of TGF-beta soluble receptor (TR) would minimise the BL induced lung fibrosis in hamsters. METHODS: The effect of a recombinant TR (TGFbetaRII) on the lung collagen accumulation was evaluated in a BL hamster model of pulmonary fibrosis. Animals were divided into four groups and intratracheally injected with saline or BL at 6.5 U/4 ml/kg followed by intratracheal instillation of phosphate buffered saline (PBS) or 4 nmol TR in 0.3 ml twice a week. Twenty days after the first intratracheal instillation the hamsters were killed for bronchoalveolar lavage (BAL) fluid, biochemical, and histopathological analyses. RESULTS: Treatment of hamsters with TR after intratracheal instillation of BL significantly reduced BL induced lung fibrosis as shown by decreases in the lung hydroxyproline level and prolyl hydroxylase activity, although they were still significantly higher than those of the saline control. Histopathological examination showed a considerable decrease in BL induced fibrotic lesions by TR treatment. However, TR did not prevent the BL induced increases in total cells and protein in the BAL fluid. CONCLUSIONS: These results suggest that TR has antifibrotic potential in vivo and may be useful in the treatment of fibrotic diseases where increased TGF-beta is associated with excess collagen accumulation. (+info)