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Biomedical subjects

J S Lea

Publications and source records attributed to J S Lea.

12 recordsLinked to original sources

Optimum screening interventions for gynecologic malignancies.

The availability of screening modalities and improvements in prevention have reduced the risk of developing some cancers over the last few decades. Methods for optimal screening of gynecologic cancers are still being investigated. Cervical cancer is the only gynecologic malignancy for which a screening modality is widely accepted and recommended to all women. Annual screening of cervical cells has been shown to reduce the incidence of cervical cancer by 78%. Unfortunately, more than 50% of cervical cancers occur in women who have not been screened optimally. In the year 2000, an estimated 12,800 women developed cervical cancer. Of these women, 89% were seen by a physician but not screened. Vaginal cancer is associated with a similar etiology, pathobiology, and symptomatology as is cervical cancer. Vaginal dysplasia and cancer can also be detected by the Pap test, but the prevalence of the disease is low. Endometrial carcinoma is the most common gynecologic cancer. The widespread availability of outpatient biopsy devices has been the most significant advance in the early diagnosis of corpus cancers. Ovarian cancer is the gynecologic malignancy associated with the highest death rate. No modality has been shown as an effective screening method for this cancer. Women with a family history of ovarian cancer may benefit from combined modality screening; prophylactic oophorectomy should be offered to those with hereditary ovarian cancer syndromes. A complete physical examination by the physician offers the best method for early detection of vulvar cancer. Awareness and implementation of recommended screening guidelines for gynecologic cancers by primary care and specialty physicians can decrease the incidence and mortality of cervical cancer. Including the genital tract in the complete examination of the female patient could decrease markedly the mortality from the other gynecologic cancers.

Adult↗

Complete groin lymphadenectomy with preservation of the fascia lata in the treatment of vulvar carcinoma.

OBJECTIVE: The goal of this study was to assess the local groin recurrence of vulvar carcinoma in patients treated by complete groin node dissection with preservation of the fascia lata (GNDPFL). METHODS: This study is a retrospective chart review of 60 patients with Stage I-IV vulvar carcinoma who underwent radical vulvectomy and GNDPFL between 1990 and 1998. All superficial inguinal nodes and the deep femoral nodes on the anterior and medial surfaces of the femoral vein within the fossa ovalis were removed en bloc while sparing the fascia lata and the cribriform fascia over the femoral artery. RESULTS: Of the 60 study patients, 14 patients had Stage I disease, 20 Stage II, 21 Stage III, and 5 Stage IV. The mean number of nodes removed was 10 per groin. Thirty-nine patients had benign nodes on groin dissection. None of these 39 patients developed cancer recurrence in the dissected groins. Twenty-one of the sixty study patients (34%) had malignant nodes on groin dissection. Of these 21 patients, 2 experienced cancer recurrence in the groins. Our study describes a groin recurrence rate of 7.6% in patients with fewer than three malignant unilateral groin nodes. Postoperatively, 13% of patients developed lymphedema and 15% formed lymphoceles. CONCLUSIONS: The zero groin recurrence rate in patients with negative nodes and the low rate of recurrence in patients with positive nodes indicate that groin lymphadenectomy with preservation of fascia lata is complete, therapeutic, and comparable to radical techniques of lymphadenectomy involving skeletonization of femoral vessels, resection of fascia lata, and muscle transposition.

Adult↗

Comparison of the structural and cytotoxic activity of novel 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone analogues.

Eight analogues of 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone have been synthesized and tested for cytotoxicity against four different leukemic and lymphomic cell lines. For K562 and BSM cells, the toxicity could be correlated with the ease of reduction of the compounds as determined by the one-electron reduction potentials and the electron spin resonance detection of the reduced compounds produced by the cells. The cell toxicity could also be correlated with the efficiency of the compounds to form cross-links in DNA. However, no such correlations could be observed for the L1210 and Raji cells, although the activity of the NADPH dependent reducing enzymes in these cells was similar to that in the others. It is believed that for the L1210 and Raji cells, the influx/efflux of the different compounds may be more important to the cytotoxicity than their reduction or alkylation.

Animals↗

Contrasting cytotoxic mechanisms of similar antitumour diaziridinylbenzoquinones.

The mechanisms of cytotoxicity of the antitumour diaziridinylbenzoquinones, AZQ and BZQ, have been investigated. HPLC analysis has been used to study the products as well as the rate of decomposition of acid-assisted ring-opening in aqueous medium as a function of pH. Microconcentrators with a molecular weight cutoff of 30 kDa were utilised to study the covalent binding of both compounds to calf thymus DNA. Radical production of both compounds in K562 cell incubations was followed using ESR and their uptake into K562 cells was monitored using radiolabelled compounds. The results show that these two diaziridinylbenzoquinones, although very similar in structure, have diverse mechanisms of cytotoxicity. The implications of these findings are discussed in the light of antitumor action.

Alkylating Agents↗

The reductive deglycosylation of adriamycin in aqueous medium: a pulse radiolysis study.

The free radical (II) produced by one-electron reduction of adriamycin (I) exists in aqueous solution at pH 7.0 in equilibrium with the parent and the two-electron reduced form (III). Over some hundreds of milliseconds deglycosylation takes place yielding an aglycone (IV) which subsequently rearranges to form a more stable aglycone, 7-deoxyadriamycinone (V). The changes in the optical absorption spectrum accompanying these processes are reported. The rate constant for III----IV is 1.1 s-1 and for IV----V is 1.5 x 10(-2) s-1. At pH 4.0 the two electron reduced form of adriamycin exists predominantly in a different tautomeric form (VII). It is suggested that this deglycosylates via a free radical mechanism involving the acidic form of the semiquinone free radical (VI).

Chemical Phenomena↗

The ESR detection of irradiated food.

Previous work has shown that the calcified tissues in several foods give rise to characteristic ESR spectra on irradiation. Further foods have now been examined. Mussel and crab shells give large signals, compared with bones of poultry, beef or frog, while prawn cuticle gives a smaller signal. The limits of detection of irradiation vary between species but are below the doses likely to be used commercially. Quantitative estimation of dose can be achieved by re-irradiation and extrapolation to zero signal.

Electron Spin Resonance Spectroscopy↗

The lack of correlation between toxicity and free radical formation of two diaziridinyl benzoquinones.

L1210 and K562 leukaemic cells have been used to study the relationship between cytotoxicity and free radical production by two aziridinyl benzoquinones, 2,5-bis(carboethoxyamino)3,6-diaziridinyl-1,4-benzoquinone (AZQ) and 2,5-bis(2-hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone (BZQ). BZQ showed a high level of toxicity in both cell lines, but no ESR signal was detectable, while AZQ readily produced an ESR signal but much lower cytotoxicity was observed, particularly in L1210 cells. The rate of superoxide formation was measured for each drug. The results demonstrate that cell killing and free radical production do not necessarily concur.

Antineoplastic Agents↗

A comparison of the free radical properties of several anthracycline anti-tumour drugs and some of their analogues.

NADPH consumption and esr spectroscopy have been used to study the rate of formation and signal intensity of free radicals produced by various anthracycline anti-tumour drugs in rat liver microsomal extract. The drugs investigated were Adriamycin, 4'Deoxyadriamycin, Daunorubicin, 4 Demethoxydaunorubicin and Carminomycin. Pulse radiolysis was also used to determine the case of reduction of each of the analogues to its semiquinone radical and some kinetic properties of the radicals produced. It is believed that the occurrence of reactions other than dismutation could be responsible for the shortened lifetimes of the semiquinone radicals observed in biological systems.

Animals↗

The reduction of anti-tumour diaziridinyl benzoquinones.

The properties of the semiquinone radicals produced for 2,5-bis(carboethoxyamino)-3,6-diaziridinyl-1,4-benzoquinone (AZQ) and 2,5-bis(2-hydroxyethylamino)-3,6-diaziridinyl-1,4-benzoquinone (BZQ), have been investigated. AZQ semiquinone radicals can be produced from the reduction of AZQ by superoxide radicals, whereas BZQ semiquinone radicals are unstable in the presence of oxygen. The one-electron reduction potentials of the couples Q/Q-. at pH 7.0 were determined as -70 +/- 10 mV for AZQ and -376 +/- 15 mV for BZQ. The difference in these potentials is explained. As a consequence of ESR studies on the enzymatically produced radicals, we have considered the factors which determine the detection of ESR signals for reduced quinones produced in a biological system.

Antineoplastic Agents↗

Structure and mobility of electron gain and loss centres in proteins.

Radiation damage to proteins is a topic of intense interest to those involved in radiation effects in biology, and also to those involved in radiotherapy. Although it has been widely studied, fundamental processes in protein damage are very hard to specify because of the complexity of the final damage products. But the non-invasive technique of electron-spin resonance is ideally suited to the task of detecting and identifying the primary and secondary products as these are expected to contains unpaired electrons (that is, free-radicals) and such species are uniquely detected by this sensitive form of spectroscopy. Our present study shows that a major radical species formed by electron loss in a range of proteins is the backbone amido radical, -N.(CO)-, characterized by hyperfine coupling to one 14N nucleus. These centres are efficiently trapped in proteins at low temperatures. In contrast, the expected backbone electron-capture centres, -NH(CO.-)-, are not readily trapped and electron transfer occurs until the ejected electron is trapped by some electrophilic centre. Such electron mobility was in fact established in our previous work on oxyhaemoglobin (FeO2----FeO2-), superoxide dismutase (Cu(II)----Cu(I] haemocyanin (Cu(II)O2Cu(I)----Cu(I)O2Cu(II] and various proteins containing S-S bonds (-S-S-)----(-S.-S-) (refs 1-4 respectively). This is strongly supported by our observation that such electrons are captured by DNA molecules, giving T.- centres, when nucleohistones are irradiated, and that Fe(CN)3-(6) ions readily scavenge such electrons from proteins which are devoid of highly electrophilic centres.

Electron Spin Resonance Spectroscopy↗

Electron transfer from protein to DNA in irradiated chromatin.

Irradiation of dry or fully hydrated frozen DNA systems (conditions of direct damage) has been shown by electron-spin resonance spectroscopy to give rise to electron-gain centres localized on thymine (T.-) and electron loss centres ('holes') localized on guanine (G.+) with approximately equal yields. Our parallel studies on the development of both single- and double-strand breaks under comparable conditions provide good evidence that these radical centres are the precursors to such damage, and we and others have argued that this may be of relevance to the damage pathways in vivo. We now report evidence that when DNA is complexed to proteins as it is in the nuclei of eukaryotes, electron transfer from the histone to DNA is facile, leading to a significant increase in the yield of electron-gain centres in DNA as judged from their electron-spin resonance spectra. In contrast 'holes' generated in the protein are trapped and do not lead to any detectable increase in the yields of G.+.

Animals↗