[Early diagnosis of prostatic cancer with digital rectal examination, PSA determination, and endorectal echography. Correlations with the morphologic diagnosis in 200 consecutive cases]. / Diagnostic précoce du cancer de la prostate par toucher rectal, dosage du PSA et échographie endorectale. Corrélations avec le diagnostic morphologique dans 200 cas consécutifs.

The proposal of an early diagnosis of prostate cancer through mass screening with digital rectal examination (DRE), transrectal ultrasound (TRUS) and serum tumor markers remains controversial: there is no high risk population. No study has proven that mass screening reduces the mortality from prostate cancer. However, when clinical and biological data give arguments for the presence of a cancer, every patient requires a prostate biopsy. We have studied the Positive Predictive Value (PPV) of each test in a selected population: 200 men over 50 years of age in which rectal examination or PSA assay was suspicious were investigated. Without any reference to the prostate volume, we considered that the PSA level was "suspicious" when it reached 3 times the upper reference value, or 12 ng/ml. DRE was suspicious in 73%, comprising 50% with prostate carcinoma. PSA assay was suspicious in 65%, comprising 61% with prostate carcinoma. 88% of cancers had a suspicious DRE or PSA assay. TRUS was suspicious in 89%, comprising 45% with prostate carcinoma. Ultrasound guided core biopsies were performed in each case, and allowed a positive diagnosis in 42% of cases, whereas bilateral fine-needle cyto-aspirates were positive in 87% of histologically proven carcinomas. Cytology alone was positive in 3 patients with negative biopsies. Both results show that the PPV of a suspicious DRE associated with an elevated PSA level is 84%. An increased PSA level is correlated with a cancer in 61%.(ABSTRACT TRUNCATED AT 250 WORDS)

Extrapolation of animal toxicity to humans: interspecies comparisons in drug development.

Different methods for converting the dose-related toxicity of drugs from animals to humans are reviewed. Each method is analyzed with respect to its utility and limitations. Linear extrapolations from animals to humans based on body weight equivalence are shown to be inaccurate unless species-specific conversion factors are used. Extrapolations based on surface area equivalence are more accurate, do not require conversion factors, and may be used when pharmacokinetic data are not available. Ultimately, interspecies conversions are most reliable when pharmacokinetic data are available, assuming that toxic responses are comparable among species for similar blood levels. Two pharmacokinetic-based approaches may be used: direct use of plasma concentration or area under the concentration-time curve (AUC) and physiologically based pharmacokinetic (PBPK) models.

[Systematic bilateral aspiration biopsy in the screening of prostatic cancer]. / La cyto-aspiration prostatique bilatérale systématique dans le dépistage du cancer de la prostate.

Systematic fine-needle aspiration biopsies and core biopsies were simultaneously obtained on 200 patients with suspected prostatic cancer over a 12-month period. The technical aspect of cellular aspiration and fixation was carefully adjusted. 6 to 8 transrectal bilateral aspirations per patient were performed, and their results were compared to those of core biopsies guided on suspicious areas revealed by rectal examination or transrectal ultrasound. The sensitivity of aspiration for the diagnosis of prostatic cancer is 87%. The specificity is 95%, with a positivity in 3 cases of prostatic cancer in which core biopsy is negative. No cytologic specimen is inadequate for diagnosis. The correlation between cytologic and histologic patterns shows that the proportion of Gleason grade 2 decreases with the cytologic grade, whereas the proportion of Gleason grade 5 increases gradually. Both results show the importance of multiple sampling in the cytological procedure, and confirm the diagnostic value of prostatic fine-needle aspiration method.

Hemoglobin-catalyzed transformation of elliptinium acetate into electrophilic species. Evidences for oxidative activation of the drug in human red blood cells.

The anti-tumor drug N2-methyl-9-hydroxyellipticinium acetate (NMHE, Celiptium) after incubation with various N or S containing amino acids (alanine, histidine, aspartic acid, cysteine, glutathione) with hemoglobin and hydrogen peroxide or an organic peroxide (terbutylhydroperoxide) leads to the formation of the corresponding covalent binding adducts, via an oxidative activation. The formation of the covalent adduct glutathione-elliptinium was also demonstrated in human red blood cells. The importance of such process under in vivo conditions is discussed.

Physicochemical and pharmacological properties of the antitumor ellipticine derivative 2-(diethylamino-2-ethyl)9-hydroxy ellipticinium-chloride, HCl.

2-(Diethylamino-2-ethyl)9-hydroxyellipticinium-chloride, HCl (DHE), a new congener of the antitumor agent elliptinium acetate (Celiptium) (NMHE), has recently been selected for phase I clinical trials. NMHE has a methyl group at nitrogen 2 on the ellipticine ring while DHE possesses a basic diethylaminoethyl chain at this position. Compared to NMHE, the presence of the diethylaminoethyl side chain results in the following: a significant increase in the lipophilicity of the drug; no significant modification in either the binding constant values to DNA or the ability to intercalate between DNA base pairs; a marked decrease in the unwinding angle value of supercoiled DNA; and no significant change in the alteration of the catalytic activity of topoisomerase II in vitro. DHE appears to act as a simple reversible intercalating agent as shown by the selective mutagenic effect on Salmonella TA 1977 tester strain and by its inability to induce the SOS functions in a sfiA lac fusion containing Escherichia coli strain. From a pharmacological point of view, the presence of the diethylaminoethyl chain results in a 2-fold increase in the cytotoxicity to L1210 cultured cells, a strong increase in the antitumor efficiency on experimental murine tumors such as L1210 and P388 leukemia, B16 melanoma, M 5076 reticulosarcoma, and colon 38 adenocarcinoma, and finally an objective decrease in the acute and subacute toxicity in mice, rat, and macaque. The absence of significant differences in the interaction of NMHE and DHE with their potential targets in vitro leads to the hypothesis that the superiority of DHE in terms of cytotoxicity and antitumor efficiency may be due to an increase in the diffusion across cellular membrane and a more favorable biodistribution in vivo.

Isolation and characterization of the glutathione-elliptinium conjugate in human urine.

In a cancer patient given 100 mg/m2 elliptinium by intravenous infusion, the glutathione conjugate was found in urine. This metabolite was isolated after ion-exchange treatment and high performance liquid chromatography. Its structure was assessed by fast-atom bombardment mass spectrometry and comparison with an authentic sample.

Potential antitumor agents: synthesis and biological properties of aliphatic amino acid 9-hydroxyellipticinium derivatives.

Aliphatic amino acids glycine, alanine, valine, and leucine were conjugated to the antitumor drug N2-methyl-9-hydroxyellipticinium (NMHE) through a peroxidase-catalyzed oxidation reaction. NMR studies of the adducts so obtained have indicated (i) that the amino acids were linked to NMHE between the nitrogen of their primary amine and the C-10 position of the ellipticine ring and (ii) that a double bond was present between the nitrogen and the alpha-carbon of the amino acid moiety. All amino acid-NMHE adducts exhibit a higher lipophilic property than the parent compound (NMHE) directly correlated with the length of the aliphatic chain of the amino acids. The adducts interact with DNA through an intercalating process with apparent binding constant ranging from 2 X 10(5) to 5 X 10(5) M-1 at pH 7.40. The presence of the amino acid moiety linked to NMHE results (i) in a slight decrease of the cytotoxicity on L1210 cells in vitro (ID50 ranged from 0.20 to 0.50 microM) as compared to NMHE (ID50 = 0.05 microM), (ii) in a decrease of the antitumor efficiency in vivo against L1210 leukemia for leucine-NMHE and valine-NMHE (ILS at LD0/2 = 35% and 31%, respectively), (iii) in a suppression of the antitumor activity for alanine-NMHE and glycine-NMHE (ILS less than 25%), (iv) in a strong increase in the bacteriostatic activity on the quaternary ammonium sensitive Escherichia coli BL101 strain and on Salmonella typhimurium TA98 strain. The bacteriostatic effect is directly correlated with the lipophilic property of the drugs. These findings are discussed in terms of a structure-activity relationship.

Superoxide dismutase, catalase, and glutathione peroxidase in red blood cells from patients with malignant diseases.

Superoxide dismutase (SOD), catalase, and glutathione peroxidase activities have been determined in red blood cells isolated from patients with acute myelogenous leukemia, chronic lymphocytic leukemia, Hodgkin's disease, lymphosarcoma, and various visceral cancers. In all investigated cases, both catalase and glutathione peroxidase were found to be in normal ranges of activity. In the group of patients with visceral cancers, SOD activity was found to be normal as well. In contrast, SOD activity was found to be significantly increased in red blood cells from patients with acute myelogenous leukemia and lymphoproliferative syndromes. This increase in superoxide level was not related to either reticulocytosis or hypochromic anemia. No relationship was found between the SOD level and the stage, the extension of the disease, or the presence of an inflammatory syndrome. The highest SOD levels were observed in untreated patients or during the early time period of the treatment. SOD levels further decrease as a function of the increase in the duration of the treatment. These results suggest an abnormality in the regulation of the expression of the SOD gene in the pluripotent stem cells.

Superoxide dismutase assay using alkaline dimethylsulfoxide as superoxide anion-generating system.

Alkaline dimethylsulfoxide as a superoxide anion-generating system in association with cytochrome c as a superoxide anion-indicating scavenger has been used to develop a new assay for superoxide dismutase. The assay is sensitive (one unit of enzymatic activity is provided by 110 ng of purified copper-containing superoxide dismutase) and highly specific. The nature of this system prevents the usual interferences and its simplicity allows for multiple, rapid measurements of superoxide dismutase activity in biological preparations using either normal or automated procedures.

Heterocyclic Quinones. 4. A new highly cytotoxic drug: 6,7-bis(1-aziridinyl)-5,8-quinazolinedione.

With the aim of obtaining new antitumoral agents, a series of 5,8-quinazolinediones was prepared. 5-Amino-6-methoxyquinazoline was oxidized by Fremy's salt to give 6-methoxy-5,8-quinazolinedione. Nucleophilic substitution reaction at C6, electrophilic substitution at C7, and synthesis of 7-amino-6-methoxy-5,8-quinazolinedione, the parent compound of streptonigrin, were studied. These compounds were tested for cytotoxic properties on L1210 leukemia cells in vitro. One of them, 6,7-bis(1-aziridinyl)-5,8-quinazolinedione, which exhibits a high cytotoxic activity (ID50 = 0.08 microM), was further screened in standard antitumor systems, including L1210 leukemia, P388 lymphocytic leukemia, sarcoma 180, and B16 melanocarcinoma. This drug gives a significant antitumoral effect on P388 leukemia but is inactive on other experimental models. Moreover, this compound was found to be highly mutagenic for Salmonella typhimurium TA98 and TA100 strains (Ames test), suggesting that DNA damage could be responsible for its cytotoxicity.