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Biomedical subjects

R L Souhami

Publications and source records attributed to R L Souhami.

At least 55 records · Page 3Linked to original sources
PubMed1994

Chemotherapy dose intensity in small cell lung cancer.

The evidence that increasing the dose intensity of chemotherapy in SCLC improves survival is reviewed. The paucity of randomized trials, the failure to report delivered dose and the methodological problems in presenting dose intensity data, mean that at present no firm conclusions can be drawn about potential survival benefit with increasing intensity of treatment. It seems possible that increases in survival can be obtained with increased intensity of chemotherapy but the degree is likely to be small and the size of randomised trials must therefore be large.

Antineoplastic Agents↗
PubMed1994

Metabolism of ifosfamide during a 3 day infusion.

Urinary drug metabolites were measured in 21 patients receiving ifosfamide by continuous infusion over 3 days. Mean values for the proportion of drug excreted as parent compound, 2-dechloroethylifosfamide (2-DC), 3-dechloroethylifosfamide (3-DC), carboxyifosfamide (CX) and ifosforamide mustard (IPM) were 19, 6, 10, 7 and 8% of dose respectively. The proportion of urinary drug products in the form of ifosfamide fell considerably over the course of the 3 days. This was mirrored by an increase in the proportion of 2-DC, 3-DC and CX. The proportion in the form of IPM, however, remained unchanged. With successive cycles the amount of 2-DC and IPM increased by about 10% per course. A very wide variation in the amount of each metabolite was reproducibly seen between patients, but no evidence for a genetic polymorphism was found. Urinary dechloroethyl metabolites correlated positively with each other and negatively with CX. Although autoinduction increases 'activation' of ifosfamide when given over 3 days, our evidence suggests that competing metabolic pathways prevent an increase in the amount of active metabolite formed.

Adenocarcinoma↗
PubMed1994

Cellular pharmacology of novel C8-linked anthramycin-based sequence-selective DNA minor groove cross-linking agents.

The cellular pharmacology of a series of C8-linked pyrrolobenzodiazepine dimers with polymethylene linkers of n = 3-6 (compounds 1-4) has been studied in a range of human tumour cell lines. The four compounds showed the same pattern of relative activity in five ovarian carcinoma cell lines and one cervical carcinoma cell line with the order of IC50 values of 1 < or = 3 < 4 < 2, which correlated with the previously demonstrated DNA interstrand cross-linking ability of the compounds in plasmid DNA. In human leukaemic K562 cells the agents produced a block in the G2/M phase of the cell cycle characteristic of cross-linking drugs, and extensive interstrand cross-linking was observed in cells by alkaline elution with no evidence of single-strand breaks. Cross-links continued to increase up to 24 h following a 1 h exposure to drug, and no repair was evident by 48 h. In a series of ovarian and cervical carcinoma cell lines with acquired resistance to cisplatin no cross-resistance to the most potent compound 1 was observed in two lines whose major mechanism of resistance to cisplatin was reduced platinum transport. Cross-resistance to 1 was observed in a cell line (A2780cisR) possessing elevated glutathione, and depletion of intracellular glutathione using D,L-buthionine-S,R-sulphoximine (BSO) from 10.25 nmol to 2.8 nmol 10(-6) cells reduced the level of resistance from 11-fold to 2-fold compared with sensitive cells. Cross-linking in the resistant cells was restored to 80% of the level in the parent line by BSO pretreatment. There was also a correlation between glutathione levels and sensitivity to 1 measured in several other ovarian cell lines. Compound 1 also showed cross-resistance in the doxorubicin-resistant cell line 41MdoxR and partial cross-resistance in CH1doxR cells. Both these lines possess elevated levels of p170 glycoprotein. Following treatment with 6 microM verapamil, the resistance in these lines decreased almost 2-fold and 8-fold respectively.

Anthramycin↗
PubMed1994

The selection of antibodies for targeted therapy of small-cell lung cancer (SCLC) using a human tumour spheroid model to compare the uptake of cluster 1 and cluster w4 antibodies.

Spheroids of a small-cell lung cancer (SCLC) cell line POC were used to evaluate the uptake and penetration of two antibodies recognising different SCLC antigens. Spheroids approximately 300-400 microns in diameter were incubated with 1 microgram ml-1 125I-labelled NY.3D11, an antibody which reacts with the cluster 1 group antigen (neural cell adhesion molecule; NCAM) and [125I]SWA11, which binds to the cluster w4 antigen. The rate of uptake of both antibodies was similar; an initially rapid phase was seen during the first 8 h and maximum uptake occurred by 24 h. The mean uptake per spheroid at 24 h was 0.97 ng for [125I]NY.3D11 and 0.45 ng for [125I]SWA11. An objective measurement of antibody penetration into spheroids was developed using a computerised image analysis of immunostained sections of spheroids. The concentration of antibody and incubation times were varied. Both antibodies penetrated the spheroids to a depth of 50 microns after 30 min. This increased to about 100 microns after 4 h incubation with 1 or 100 micrograms ml-1 SWA11. The results with 1 microgram ml-1 NY.3D11 were similar, but in the presence of 100 micrograms ml-1 NY.3D11 penetration into the spheroid was deep and diffuse. These results demonstrate a major concentration-dependent difference in the uptake and penetration of cluster 1 and cluster w4 antibodies in this spheroid model and they have implications for the selection of antibodies for targeted therapy of SCLC.

Antibodies, Monoclonal↗
PubMed1994

Received dose-intensity: a randomized trial of weekly chemotherapy with and without granulocyte colony-stimulating factor in small-cell lung cancer.

PURPOSE: A prospective randomized trial to determine if granulocyte colony-stimulating factor (G-CSF) could increase the received dose-intensity (RDI) of weekly chemotherapy in patients with small-cell lung cancer (SCLC). PATIENTS AND METHODS: Forty patients with SCLC with good prognostic features (all patients with limited disease [LD], and extensive-disease [ED] patients with Eastern Cooperative Oncology Group [ECOG] 0 or 1 and plasma alkaline phosphatase levels < 1.5 times the upper limit of normal) were randomized to receive weekly chemotherapy with or without G-CSF. G-CSF (5 micrograms/kg) was self-administered subcutaneously on days when chemotherapy was not given. Chemotherapy consisted of cisplatin 50 mg/m2 intravenously (IV) on day 1 and etoposide 75 mg/m2 IV on days 1 and 2 alternating weekly with ifosfamide 2 g/m2 IV (with mesna) and doxorubicin 25 mg/m2 on day 1, for a total of 12 courses. Dose modifications (dose reductions and treatment delays) were made according to defined hematologic criteria. RESULTS: Dose reductions were made at some point during treatment in 12 of 17 patients in the control arm and in 11 of 23 patients in the G-CSF arm (P = .20). The proportion of patients experiencing dose reductions due to leukopenia was significantly higher in the control arm (nine of 17) compared with the G-CSF arm (four of 23, P < .04). Cycle delays due to leukopenia were similar in both arms of the study. The RDI was 82% of projected in the control arm (95% confidence interval [CI], 79% to 84%) and 84% in patients receiving G-CSF (95% CI, 82% to 87%) (P value not significant). CONCLUSION: In this randomized trial, G-CSF significantly decreased dose reductions due to neutropenia. However, administration of G-CSF did not decrease dose reductions or treatment delays to a level that would allow an increase in received dose-intensity. Nonhematologic toxicities such as increased creatinine concentration also prevented an increase in the RDI in the G-CSF arm.

Adult↗
PubMed1994

Randomized trial comparing weekly versus 3-week chemotherapy in small-cell lung cancer: a Cancer Research Campaign trial.

PURPOSE: A randomized trial of chemotherapy, given on either a 1-week or a 3-week schedule, was performed in small-cell lung cancer (SCLC) patients. The aim was to determine if weekly scheduling produced survival superior to conventional treatment. PATIENTS AND METHODS: Four hundred thirty-eight patients with SCLC with either limited disease (LD; 276 patients) or good-prognosis extensive disease (ED; 162 patients) were randomized. Weekly chemotherapy was 12 alternating cycles of ifosfamide/doxorubicin and cis-platin/etoposide (PE), while 3-week treatment was six alternating cycles of cyclophosphamide/doxorubicin/vincristine (CAV) and PE. Thoracic irradiation was administered 3 weeks after completion of chemotherapy to LD patients who attained a complete response (CR) or partial response (PR). Patients were well matched for clinical characteristics and prognostic factors. RESULTS: Overall response was the same in both arms: 82.3% (39.4% CR) with weekly and 81.1% (36.9% CR) with 3-week treatment. The median survival (MS) durations were 10.8 and 10.6 months for weekly and 3-week chemotherapy, respectively. The 2-year survival rates were 11.8% and 11.7% in the weekly and 3-week arms, respectively. Received dose-intensity (DI) was 73.9% of projected for weekly treatment and 92.7% for 3-week treatment. Hematologic toxicity was the major dose-limiting toxicity for the weekly treatment. CONCLUSION: This trial excludes at 90% power a benefit of greater than 10% for 2-year survival for weekly treatment. The received DI was reduced to a greater extent with weekly treatment, mainly due to hematologic toxicity.

Adult↗
PubMed1994

Doxorubicin and cisplatin with granulocyte colony-stimulating factor as adjuvant chemotherapy for osteosarcoma: phase II trial of the European Osteosarcoma Intergroup.

PURPOSE: This report describes the toxicity and feasibility of administering doxorubicin (DOX) and cisplatin (CDDP) at 2-week intervals with granulocyte colony-stimulating factor (G-CSF) to patients with osteosarcoma and the compatibility of this regimen with endoprosthetic surgery performed after three cycles. PATIENTS AND METHODS: Twenty-four patients with biopsy-proven osteosarcoma were treated with three preoperative cycles of DOX 25 mg/m2/d on days 1 to 3 and CDDP 100 mg/m2 on day 1 with G-CSF 5 micrograms/kg/d on days 4 to 14. Surgery was scheduled at week 6 to be followed by three further cycles of chemotherapy at 2-week intervals. RESULTS: Two-week chemotherapy was feasible, but delays and dose reductions only allowed 74% and 78% of the intended dose-intensity of DOX and CDDP to be administered. Thrombocytopenia accounted for 50% of delays. Significant toxicity included neutropenic sepsis, severe mucositis, prolonged nausea and vomiting, and electrolyte disturbances. Twenty-one limb-salvage procedures and one amputation were performed. There were eight episodes of excessive perioperative bleeding. CONCLUSION: Intensive 2-week chemotherapy with intercurrent surgery is feasible and allows a greater dose-intensity of chemotherapy to be administered compared with the same regimen administered at 3-week intervals without G-CSF. The toxicity is considerable, but manageable.

Adolescent↗
PubMed1994

Structure-activity relationship of a series of nitrogen mustard- and pyrrole-containing minor groove-binding agents related to distamycin.

Two series of tethered nitrogen mustards based on the minor groove-binding and A/T sequence-specific natural product distamycin have been synthesized and evaluated. The conjugates, which have a modified dimethylamino C-terminus, are comprised of one, two or three pyrrole carboxamide units linked to either benzoic acid mustard (BAM) or chlorambucil (CHL). The DNA binding properties, in vitro cytotoxicities and DNA cross-linking abilities were determined for each of the conjugates. The conjugates were found to bind preferentially to poly(dA.dT) compared to poly(dG.dC) DNA by ethidium displacement and circular dichroism. The di- and tripyrrole conjugates had higher binding affinities than the monopyrrole conjugates. All the conjugates were more cytotoxic than the nitrogen mustards themselves. Cytotoxicity increased with the increase from one to three pyrrole units and the CHL conjugates were more cytotoxic than the corresponding BAM analogues. The CHL conjugates were able to cross-link plasmid DNA at a 10-fold lower dose than CHL itself. The BAM conjugates showed < 10% cross-linking at doses which gave 100% cross-linking with the CHL conjugates. In cells, the CHL conjugates showed significant cross-linking at the IC50 values, while the BAM conjugates showed no evidence of cross-link formation even at 10 times the IC50 value. These results are discussed in reference to a series of previously reported GC-recognizing imidazole analogues possessing the same nitrogen mustard groups.

Alkylating Agents↗
PubMed1993

Electrophoretic and chromatographic separation methods used to reveal interstrand crosslinking of nucleic acids.

Several electrophoretic and chromatographic techniques, many of which have only been developed recently, provide sensitive methods for the detection and separation of DNA containing interstrand crosslinks such as those produced by many cancer chemotherapeutic drugs and photoactive psoralen derivatives. Most of the methods rely on the fact that the presence of such crosslinks prevent the complete denaturation of the two complimentary DNA strands by heat or alkali. A simple and highly sensitive neutral agarose gel electrophoresis method is particularly applicable to detailed time-course experiments of both total crosslink formation, and the "second-arm" of the crosslink reaction. This method separates denatured single-stranded from double-stranded DNA which has reannealed as a result of an interstrand crosslink. Polyacrylamide gel-based assays using denaturing gels are more suited to the separation of smaller crosslinked DNA fragments and, in particular, small oligonucleotides on high-percentage gels. In addition, they provide methods for the determination of the exact base position and sequence selectivity of crosslink formation. Sephadex chromatography and high-performance liquid chromatography can separate small crosslinked oligonucleotides from non-crosslinked duplexes, and the hydroxyapatite column chromatographic separation of single- and double-stranded cellular DNA can be used to quantitate the level of interstrand crosslinking present in the bulk of the genome. Finally, the analysis of damage by crosslinking agents, and its repair, at the level of specific genes can be achieved by hybridization with specific probes following membrane transfer from neutral agarose gels used to fractionate restricted and fully denatured genomic DNA from drug-treated cells.

Animals↗
PubMed1993

Two structurally related diaziridinylbenzoquinones preferentially cross-link DNA at different sites upon reduction with DT-diaphorase.

The nucleotide sequence preferences for the formation of interstrand cross-links induced in DNA by 2,5-diaziridinyl-1,4-benzoquinone (DZQ) and 3,6-dimethyl-2,5-diaziridinyl-1,4-benzoquinone (MeDZQ) were studied using synthetic duplex oligonucleotides and denaturing polyacrylamide gel electrophoresis (PAGE). Reaction of these bifunctional alkylating agents with a DNA duplex containing several potential cross-linking sites resulted in the formation of cross-linked DNAs with different electrophoretic mobilities. Analysis of the principal cross-linked products by piperidine fragmentation revealed that the preferential site of cross-linking was altered from a 5'-GNC to a 5'-GC sequence upon reduction of DZQ to the hydroquinone form by the enzyme DT-diaphorase. In contrast, the reduced form of MeDZQ was found to preferentially cross-link at 5'-GNC sites within the same sequence. These preferences were confirmed in duplex oligonucleotides containing single potential cross-linking sites. Additional minor cross-linked products were characterized and revealed that DZQ and MeDZQ are both capable of cross-linking across four base pairs in a 5'-GNNC sequence.

Alkylation↗
PubMed1993

Pharmacokinetics of 10-ethyl-10-deaza-aminopterin, edatrexate, given weekly for non-small-cell lung cancer.

We studied the pharmacokinetics of 10-ethyl-10-deaza-aminopterin (10-EdAM), edatrexate and its 7-hydroxy metabolite during a phase II trial of treatment in advanced non-small-cell lung cancer. A dose of 80 mg/m2 was given weekly, with dose reduction being undertaken for mucositis or haematological toxicity. A triphasic pattern of plasma elimination was seen, the mean half-lives being 0.10 +/- 0.07, 0.8 +/- 0.3 and 7 +/- 7 h, respectively. The mean plasma clearance was 25 +/- 14 l/h, with 18% +/- 11% of the dose appearing unchanged in the urine. The serum concentration at 1 h accurately predicted the area under the curve (AUC) with r2 = 0.976. There was considerable variation of the clearance both within and between patients but there was no evidence of a dependence on time or dose. The 1-h concentration of the drug was shown to be related to the incidence of toxicity requiring dose reduction. The change in WBC due to the initial dose was shown to be related to both the AUC of the drug and that of its 7-OH metabolite.

Aminopterin↗
PubMed1993

Patient compliance with prolonged low-dose oral etoposide for small cell lung cancer.

Using an 'intelligent' tablet bottle which, unknown to the patient, electronically records the times of opening we have assessed the compliance of patients with prescribed oral medication. The compliance pattern of 12 patients receiving low dose etoposide for small cell lung cancer was monitored over 25 treatment periods, representing a total of 298 days. The data were expressed as overall compliance (OC), defined as the observed number of bottle openings as a percentage of the prescribed number of doses, and as two indices representing daily and hourly irregularities in the times of opening. The OC had a mean (+/- s.d.) value of 93.2% (+/- 12%) over the 25 treatment periods, and is similar to that which we have reported in a group of lymphoma patients (Lee et al., 1992). By means of a self assessed diary card we monitored the physical and mental state of the patients. Although we found significant associations between the compliance measures and some of the diary card measures, the magnitude of the observed effects would be of little practical consequence. We conclude that, in our group of patients, inadequate compliance with oral chemotherapy would not account for any significant lack of clinical response.

Carcinoma, Small Cell↗