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Biomedical subjects

R L Souhami

Publications and source records attributed to R L Souhami.

At least 91 records · Page 5Linked to original sources
PubMed1991

DNA interstrand crosslinking and sequence selectivity of dimethanesulphonates.

Members of the homologous series of alkanediol dimethanesulphonates of general formula H3C.SO2O.(CH2)n.O.SO2.CH3 have been tested for their ability to produce DNA interstrand crosslinking and DNA sequence selectivity of guanine-N7 alkylation. In a sensitive crosslinking gel assay the efficiency of DNA interstrand crosslink formation, dependent on the ability of the alkylating moiety to span critical nucleophilic distances within the DNA, was found at 6 h to be 1,6-hexanediol dimethanesulphonate (Hexa-DMS) (n = 6) greater than methylene dimethanesulphonate (MDMS) (n = 1) greater than 1,8-octanediol dimethanesulphonate (Octa-DMS) (n = 8) greater than Busulphan (n = 4). The DNA interstrand crosslinking produced by MDMS was not due to either of its hydrolysis products, formaldehyde or methanesulphonic acid (MSA). In contrast the extent of monoalkylation at guanine-N7 as determined by a modified DNA sequencing technique was found to be Busulphan much greater than Hexa-DMS = Octa-DMS, with a sequence selectivity somewhat less than that of other chemotherapeutic alkylating agents such as nitrogen mustards. MDMS at high levels induced a non-specific depurination as a result of the reduction in pH resulting from MSA release. More strikingly MDMS (and MSA) produced a single strong site of guanine reaction (depurination) in a guanine-rich 276 base pair fragment of pBR322 DNA in the sequence of 5'-ATGGTGG-3'. This was observed when non-specific depurination was negligible and was not seen with formic acid. Thus structurally similar alkylating agents can differ in their type and extent of DNA monoalkylation and interstrand crosslinking, and in some cases (e.g. MDMS/MSA) produce reactions with a high degree of selectivity.

Alkylation↗
PubMed1991

Intensive weekly chemotherapy for good-prognosis patients with small-cell lung cancer.

A weekly, intensive chemotherapy regimen has been used to treat 70 patients with small-cell lung cancer (SCLC). Forty-five patients had limited disease (LD) and 25 extensive disease (ED) with good prognostic features. The regimen consisted of cisplatin 50 mg/m2 intravenously (IV) day 1 and etoposide 75 mg/m2 IV days 1 and 2, alternating weekly with ifosfamide 2 g/m2 IV day 8 and doxorubicin 25 mg/m2 IV day 8, for a total of 12 weeks. Dose modifications were made according to defined hematologic criteria. Responding patients with limited disease subsequently received mediastinal radiotherapy. Overall response to chemotherapy was 91% with a complete response (CR) rate of 50%. Forty-five patients with limited disease (LD) achieved an overall response rate of 91% with a CR rate of 51%, and 25 patients with extensive disease (ED) achieved an overall response rate of 92% with a CR rate of 48%. Median survival for the whole group was 54 weeks (LD, 58 weeks; ED, 42 weeks). Hematologic toxicity was predictable, without the wide fluctuations in WBC count seen in conventional 3-weekly regimens. In all, one quarter of treatment courses were delayed, most frequently because of leukopenia. Dose reductions were required in 63% of cases. The average delivered dose intensity was calculated and shown to be 73% of projected. Nonhematologic toxicity was mild with nausea and vomiting being the most common. This weekly schedule of chemotherapy has proved to be active and well tolerated and is currently being compared with conventional 3-weekly chemotherapy in a randomized study.

Adult↗
PubMed1991

A randomized trial of carboplatin versus iproplatin in untreated advanced ovarian cancer.

Between August 1984 and October 1987, 120 patients with stage IC to IV epithelial ovarian cancer were randomly assigned to receive carboplatin (400 mg/m2) or iproplatin (300 mg/m2) every 4 weeks as initial treatment. Stratification was made according to International Federation of Gynecology and Obstetrics (FIGO) stage and according to size of residual disease after surgery. Response was evaluated after six courses when patients were restaged, with laparoscopy or laparotomy in clinical complete responders or those with no assessable disease. Treatment was then stopped in surgically proven complete responders. Patients with partial (PR) or minor response (MR) received a further six courses of their original drug at a reduced dose (carboplatin 300 mg/m2, iproplatin 225 mg/m2). Patients with stable (SD), progressive (PD), or recurrent disease were treated with cyclophosphamide (1 g/m2). The response rates were 63% (95% confidence interval [CI], 50% to 74%) for carboplatin and 38% (95% CI, 26% to 51%) for iproplatin. Fifteen patients were not assessable for response. The median survival was 114 weeks (95% CI, 82 to 233 weeks) for carboplatin patients and 68 weeks (95% CI, 48 to 82 weeks) for iproplatin patients (P = .008). The amount of residual disease after initial laparotomy was a prognostic factor for survival. Myelosuppression was the main toxicity and was greater with iproplatin. This study shows carboplatin to be more active than iproplatin in the treatment of ovarian cancer and less toxic. Few responses to cyclophosphamide occurred following either drug, implying resistance to the alkylating agent.

Adult↗
PubMed1991

Results of the central data analysis.

This chapter presents the results of blind serological studies carried out by workshop participants on 87 monoclonal antibodies (mAbs) supplied to them as a coded panel. Twenty six mAbs had been studied in the first workshop. Participants were asked to carry out immunohistochemical, immunocytological or flow cytometric analysis on a mandatory panel of target tissues or cells. Central computer analysis and other supporting data allowed the assignment of 33 mAbs to seven clusters. Two of the antigens identified have been cloned while two more have been defined as carbohydrate epitopes. The results allow comparison of new mAbs against lung cancer with existing ones and are beginning to provide a description of the antigenic structure of the SCLC cell surface.

Antibodies, Monoclonal↗
PubMed1990

Depletion of cellular glutathione by N,N'-bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea as a determinant of sensitivity of K562 human leukemia cells to 4-hydroperoxycyclophosphamide.

N,N'-Bis(trans-4-hydroxycyclohexyl)-N'-nitrosourea (BHCNU) is a nitrosourea which has carbamoylating but not alkylating activity. It has been shown to carbamoylate and inactivate glutathione reductase thereby reducing the intracellular levels of glutathione (GSH). Since GSH depletion by buthionine-S,R-sulfoximine potentiates the cytotoxicity of cyclophosphamide, with a corresponding increase in DNA cross-linking, we have investigated the potential interaction between BHCNU and cyclophosphamide. Treatment of K562 human leukemia cells with 15 microM BHCNU for 1 h resulted in depletion of glutathione to 40% of control values, without significant reduction of cell viability. Subsequent treatment with 10 microM 4-hydroperoxycyclophosphamide (4-HC), a self-activating derivative of cyclophosphamide, reduced the level of glutathione to less than 20% of control values. BHCNU pretreatment enhanced the cytotoxicity of 4-HC resulting in a dose modification factor of 2.5. Alkaline elution analysis of cellular DNA demonstrated that the level of interstrand cross-linking was 2-fold higher in GSH-depleted cells than in nondepleted cells, and the induction of single strand breaks was markedly increased. These findings demonstrate that BHCNU potentiates the cytotoxicity of 4-HC and suggest that this is due to the increased formation of DNA interstrand cross-links caused by a reduced intracellular conjugation of 4-HC with glutathione which results in an increased binding of 4-HC to DNA targets.

Cross-Linking Reagents↗
PubMed1990

Effect of ionic strength and cationic DNA affinity binders on the DNA sequence selective alkylation of guanine N7-positions by nitrogen mustards.

Large variations in alkylation intensities exist among guanines in a DNA sequence following treatment with chemotherapeutic alkylating agents such as nitrogen mustards, and the substituent attached to the reactive group can impose a distinct sequence preference for reaction. In order to understand further the structural and electrostatic factors which determine the sequence selectivity of alkylation reactions, the effect of increased ionic strength, the intercalator ethidium bromide, AT-specific minor groove binders distamycin A and netropsin, and the polyamine spermine on guanine N7-alkylation by L-phenylalanine mustard (L-Pam), uracil mustard (UM), and quinacrine mustard (QM) was investigated with a modification of the guanine-specific chemical cleavage technique for DNA sequencing. For L-Pam and UM, increased ionic strength and the cationic DNA affinity binders dose dependently inhibited the alkylation. QM alkylation was less inhibited by salt (100 mM NaCl), ethidium (10 microM), and spermine (10 microM). Distamycin A and netropsin (100 microM) gave an enhancement of overall QM alkylation. More interestingly, the pattern of guanine N7-alkylation was qualitatively altered by ethidium bromide, distamycin A, and netropsin. The result differed with both the nitrogen mustard (L-Pam less than UM less than QM) and the cationic agent used. The effect, which resulted in both enhancement and suppression of alkylation sites, was most striking in the case of netropsin and distamycin A, which differed from each other. DNA footprinting indicated that selective binding to AT sequences in the minor groove of DNA can have long-range effects on the alkylation pattern of DNA in the major groove.

Alkylation↗
PubMed1990

Photosensitization of human leukemic cells by anthracenedione antitumor agents.

1,4-Diamino-substituted anthraquinone antitumor agents (mitoxantrone and ametantrone) and structurally related 1,5- and 1,8-diamino-substituted compounds (AM1 and AM2) were tested for their ability to photosensitize human leukemic cells in culture. Viability was measured using the 3,4,5-dimethylthiazol-2,5-diphenyl tetrazolium bromide assay, and DNA and membrane damage were assessed. Following a 1-h exposure to AM2, a dose of drug required to give 50% loss of cell viability (53 microM) was obtained in the dark, which was reduced to approximately 2.4 microM following illumination for 2 min (lambda greater than 475 nm), a dose of light that was completely nontoxic to the cells in the absence of drug. A shift in the cell viability curve was also observed for AM1 but, under identical conditions, the dose modification was only 8.9. In contrast, neither ametantrone nor mitoxantrone gave a decreased viability upon illumination. DNA single-strand breaks as measured by alkaline elution correlated with cell viability. Frank DNA single-strand breaks were produced by AM2 and light, suggesting the production of free radicals. The strand breaks produced by AM2 in the dark and by mitoxantrone (with or without illumination) were protein concealed. No evidence of photo-induced membrane damage, as determined by transport of the model amino acid cycloleucine, could be observed even at supralethal doses.

Antineoplastic Agents↗
PubMed1990

Mitomycin, ifosfamide and cisplatin in non-small-cell lung cancer.

Chemotherapy with mitomycin C, ifosfamide and cisplatin (MIC) is reported to produce responses of 56% and 69% in inoperable non-small-cell lung cancer (NSCLC). We evaluated the regimen in 45 similar patients who received up to six courses of 6 mg/m2 mitomycin C, 3 g/m2 ifosfamide, and 50 mg/m2 cisplatin every 3 weeks. In all, 18 patients had limited disease (LD) and 27 had extensive disease (ED). A total of 18 patients responded (40%), 9/18 with LD and 9/27 with ED; there were 4 complete responders. The median duration of response was 25 weeks, and median survival was 32 weeks (range, 2-96 weeks). Toxicity was moderate. Nausea and vomiting were controlled with i.v. dexamethasone and high-dose metoclopramide. Other toxicities included myelosuppression and alopecia. This study confirms that MIC is one of the most active regimens for treatment of NSCLC, with acceptable toxicity.

Adult↗
PubMed1990

Quality of life during chemotherapy for small cell lung cancer: assessment and use of a daily diary card in a randomized trial.

Fifty-three patients who were taking part in a randomized trial of chemotherapy in small cell lung cancer (SCLC) were entered into a study of quality of life measurement using a daily diary card. Patients received either four or eight cycles of initial chemotherapy and daily records were scored, using a four point scale of nausea, sickness, appetite, sleep, mood, pain, activity and general well being. Two hundred and fifty-six of a possible 379 cards were returned (68% compliance). The first 31 patients took part in an assessment of the diary card where comparison was made with nurse ratings using the card, the EORTC questionnaire and the Spitzer quality of life index. These comparisons showed appropriate convergent and divergent validity and demonstrated the sensitivity of the diary card to short term changes compared with the other measures. In the randomized trial the diary card demonstrated a worsening of sickness and related variables as treatment continued. This spilled over into mood and general well being although physical variables of pain, sleep and activity were largely unaffected. Prophylactic cranial irradiation was associated with a transient increase in sickness and vomiting. The study shows that the diary card is an instrument sensitive to short term changes in quality of life and thus especially useful for comparing effects during the period of treatment.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1990

Unusual bony lesions of histiocytosis X in a patient previously treated for Hodgkin's disease.

We present an unusual case of multifocal Histiocytosis X in a 78-year-old man treated for Hodgkin's Disease 33 and 24 years previously. The Hodgkin's Disease at first involved cervical nodes and 9 years later axillary and inguinal nodes and was treated by radiotherapy. Chronic destructive lesions developed in the femora and pelvis and bone biopsies showed a curious mixture of fibroblastic tissue and foamy macrophages. These lesions eventually resulted in pathological fractures of the femoral necks, and bilateral hip replacements were required seven years after initial detection of the bony lesions. There was a focal infiltrate of S-100 protein positive histiocytic cells containing Birbeck granules in the femoral heads. There was radioisotopic and radiological evidence of other skeletal lesions. The association between Histiocytosis X and Hodgkin's Disease is recognised but rare and its significance is discussed.

Adult↗
PubMed1990

Longevity in small cell lung cancer. A report to the Lung Cancer Subcommittee of the United Kingdom Coordinating Committee for Cancer Research.

An analysis of the long-term results of treatment of 3,681 patients with small cell lung cancer (SCLC) is presented. The data were obtained from major centres in the UK who were conducting treatment trials during the period 1978-1986 and for whom complete computer records and follow-up were available. A total of 217 (5.9%) survived 2 years or more. Two year survival for patients presenting with limited disease (LD) was 8.5% and for extensive disease (ED) 2.2%. Death from SCLC continued until 7 years after diagnosis but not thereafter. At this point overall survival was 3% (3.6% LD, 1.1% ED). Survival after 2 years was not affected by initial disease extent, sex, thoracic radiotherapy or prophylactic cranial irradiation. Death from causes other than SCLC continued throughout the period of observation. Vascular disease, respiratory failure and second tumours were the main other causes of death. The better survival in younger patients was mainly attributable to few deaths from these other causes. These results indicate that only a small proportion of patients with SCLC are cured by current treatment. Although shorter term improvement in survival has been obtained with current treatment, the poor overall long-term results support studies exploring new approaches to cure and to palliation.

Carcinoma, Small Cell↗
PubMed1990

The response of cerebral metastases in small cell lung cancer to systemic chemotherapy.

Although small cell lung cancer (SCLC) is very chemosensitive, cerebral metastases are treated with radiotherapy in the belief that they are protected from chemotherapy by the blood-brain barrier (BBB). The validity of this assumption has not been tested in clinical practice. In a randomised trial of treatment in 610 patients with SCLC, 19 patients who had symptomatic cerebral metastases at presentation were treated initially with chemotherapy, and cranial irradiation withheld. Chemotherapy was cyclophosphamide 1 g m-2 i.v. day 1, vincristine 2 mg i.v. day 1 and etoposide 100 mg tds p.o. days 1-3, repeated every 21 days, with response assessed objectively by computerised tomography (CT) or radionuclide brain scan, and by clinical examination. A post-chemotherapy scan was obtained in 14 patients, eight of whom achieved a partial remission and one a complete remission of the cerebral metastases. The radiologically proven responses were sustained and accompanied by rapid neurological improvement. Of the remaining five patients who were assessed by clinical examination alone, one had improved neurological function after chemotherapy. The response rate for SCLC cerebral metastases treated with chemotherapy was therefore 10/19 (53%). Chemotherapy has the advantage over cranial irradiation of simultaneously treating both cerebral metastases and extracranial disease. The place of chemotherapy in the management of cerebral metastases in this and other chemosensitive tumours should be reconsidered since these findings indicate that the BBB does not prevent response to chemotherapy.

Adult↗
PubMed1989

Intensive chemotherapy with autologous bone marrow transplantation for small-cell lung cancer.

Since 1980, 75 patients with small-cell lung cancer (SCLC) have been entered into four consecutive studies of high-dose chemotherapy using autologous bone marrow transplantation (ABMT) to assist haematological recovery. In the first study, 25 patients were treated with cyclophosphamide (160-200 mg/kg) as the sole chemotherapy; in the second (26 patients), the cycle of high-dose cyclophosphamide (with or without 800-1,200 mg/m2 etoposide) was repeated as induction treatment. In the first study, response was high [14 complete responses (CR), 7 partial responses (PR)] but was not increased by repeating the cycle (15 CR, 8 PR), and survival was slightly worse in the second trial. In the third study, 15 patients were treated with doxorubicin, vincristine and etoposide for two cycles and then with 200 mg/kg cyclophosphamide. Although high-dose cyclophosphamide increased the complete response rate, the additional responses were short-lived. In the final study, an attempt was made to increase the initial CR rate by combination chemotherapy using carboplatin (400-600 mg/m2), etoposide (120 mg/m2 x 4) and either high-dose cyclophosphamide (40 mg/kg x 4) or melphalan (140 mg/m2). Although all nine patients responded, none underwent a CR. The long-term survival (up to 7 years) does not appear to be different from that in comparably selected cases treated with conventional chemotherapy.

Antineoplastic Combined Chemotherapy Protocols↗