Mitomycin C, cisplatin, and 5-fluorouracil for advanced and/or recurrent head and neck squamous cell carcinomas.

The combination of cisplatin (CDDP 100 mg/m2 on day 1) and 5-fluorouracil (5-FU 1,000 mg/m2 continuous intravenous (i.v.) infusion days 1-5) is the most widely used chemotherapy regimen for the treatment of advanced head and neck carcinomas, with a response rate of 70-90% but with a survival and a duration of response which are not impressive. Most patients relapse in < or = 2 years and die of cancer. We evaluated the activity of a CDDP (90 mg/m2 on day 1), 5-FU (900 mg/m2/120 h continuous i.v. infusion from day 1), and mitomycin C (MMC 6 mg/m2 on day 1) regimen in advanced or recurrent head and neck squamous cell carcinoma (HNSCC). Fifty-six patients were treated and evaluated for response and toxicity: 5 (9%) complete responses (CR) and 36 (64%) partial responses, (PR) were observed (response rate 73%). The median duration of response was 12 months, and median survival was 15 months. At a median follow-up of 14 months, the estimated overall survival at 1 year was 65%; at 2 years, it was 35%. Grade 3-4 toxicity was noted in 14 patients, mostly hematologic; overall toxicity required a dose-intensity decrease in 20.2% of all cycles. No treatment-related deaths occurred. The regimen showed a good response rate and an encouraging median duration of response with a good tolerability profile.

Synthetic thymic fraction 5: effects of high dose administration on circulating lymphocytes in patients.

The synthetic pentapeptide (Arg-Lys-Asp-Val-Tyr; TP-5) corresponding to the active site of the hormone thymopoietin, was given at the dose of 300 mg/m2/day (1 day), higher than the usually administered, to a group of 27 immunodepressed patients in order to determine the tolerability and the immunomodulatory activity. The examination of a series of hematological parameters including counts of differential clustering of lymphocytes by cytofluorimetric analysis was performed 24 hr and 48 hr after treatment, and repeated at different intervals up to 14 days after treatment. TP-5 caused a significant increase of circulating lymphocytes and particularly of CD3+CD4+ and CD3+CD8+ subtypes, peaking at 48 hr and maintaining the increased values up to the last examination on day 14 from treatment. A faster increase (zenith at 24 hr) was observed for CD4+ cells, in comparison with CD8+ cells (zenith at 48 hr). The number of patients that increased total lymphocytes or lymphocyte subset after treatment ranged between 52.6 (CD4+ cells) and 69.2% (NK cells), whereas about 7.7% (NK cells) to 36.9% (CD4+ cells) remained unchanged and a smaller amount of 10.5% (CD4+ and CD8+ cells) or 23.1% (NK cells) showed a decrease greater than 10% of their respective basal value. No significant relationship between responders and non-responders can be found on the basis of previous treatments, cancer type, sex or age.

Evaluation of the circulating glycoprotein CA549 in mammary cancer and other malignancies.

A prospective study was carried out on a recent marker for breast cancer, CA549, a mucine-like acid glycoprotein present in the fat membranes of human milk. Fifty healthy control subjects and 91 with benign conditions, 103 mammary cancer patients and 256 patients with other types of malignancy were studied. For comparison, CEA and CA15-3 were also investigated. The CA549 cutoff was 11 U/ml. In breast cancer the marker was below the cutoff in 9 cases (92.8%); in malignancies other than breast cancer it was above the cutoff in 5 to 50% of patients. In breast cancer it was raised in 83.3% of cases (CA15-3 showed 82.9% and CEA 50%). In breast cancer after radical surgery, CA549 was normal in patients who were in TNM stage I but above the cutoff in 57.1% of those at more advanced stages. The follow-up study is ongoing among these patients. In all the study conditions, CA549 favorably compared to CA15-3 values, with sensitivity and specificity greater than CEA.

[Chemical and pharmacological research on pyran derivatives. VII. Derivatives of naphto/1',2':5,6/pyran/2,3-c/pyrazole and of 12H-naphto/1',2':5,6/pyran/2,3-d/pyrimidine]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota VII--derivati del nafto[1',2':5,6]pirano[2,3-c]pirazolo e della 12H-nafto[1',2':5,6]pirano[2,3-d]pirimidina

Reaction of substituted 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans with N,N-dimethylformamide in the presence of phosphorus oxychloride afforded the corresponding substituted 1-oxo-2-formyl-3-dialkyl-amino-1H-naphtho[2,1-b]pyrans. Condensation of substituted 1-oxo-2-formyl-3-dimethylamino-1H-naphtho[2,1-b]pyrans with hydrazine or monosubstituted hydrazines led to the formation of 11-oxo-8H,11H-naphtho[1',2':5,6]pyrano[2,3-c]pyrazole derivatives through the intermediate hydrazones and subsequent cyclization. Similarly, condensation with acetamidine or guanidine gave rise to the formation of 12-oxo-12H-naphtho[1',2':5,6]pyrano[2,3-d]pyrimidine derivatives. Some of these compounds were tested for their pharmacological properties, but no noteworthy activity was observed.

[1,5-Benzodiazepines. III. Synthesis of 2,4-bisdialkylamino-3H-1,5-benzodiazepines]. / Ricerche su 1,5-benzodiazepine. Nota III. Sintesi di 2,4-bisdialchilammino-3H-1,5-benzodiazepine.

Treatment of 2,3-dihydro-2-oxo-4-dialkylamino-1H-1,5-benzodiazepines with phosphorus pentasulfide afforded 2-thio derivatives which in turn gave the corresponding methylmercapto derivatives by reaction with sodium hydride and methyl iodide. By treating these compounds with dialkylamines the formation of 2,4-bisdialkylamino-3H-1,5-benzodiazepines was achieved. Pharmacological screening of some of the products indicated that the introduction of a second dialkylamino substituent into the 1,5-benzodiazepine molecule gave the compounds CNS excitant properties, while the initial monodialkylamino derivatives containing sulfur showed a CNS depressant activity.

[1,5-benzodiazepines. V. Synthesis of pyrazolo (3,4-b)(1,5)benzodiazepines and 5H-pyrimido(4,5-b)(1,5)benzodiazepines]. / Ricerche su 1,5-benzodiazepine. Nota V - Sintesi di derivati della pirazolo[3,4-b][1,5]benzodiazepina e della 5H-pirimido[4,5-b][1,5]benzodiazepina.

The reaction of 4-(dialkylamino)-1,3-dihydro-2H-1,5-benzodiazepin-2-ones (I a-c) with N,N-dimethylformamide in the presence of phosphorus pentachloride at room temperature gave rise to the formation of 4-(dialkylamino)-3-[(dimethylamino)methylene]-1,3-dihydro-2H-1,5-benzodiazepin- 2-ones (IX a-c) which were useful starting materials to achieve the synthesis of tricyclic 1,5-benzodiazepine derivatives. Actually (IX a), selected for the smallest steric hindrance of the 4-dialkylamino substituent, by reaction with hydrazines afforded pyrazolo[3,4-b][1,5]benzodiazepine derivatives whereas reaction with guanidine or amidines gave 5H-pyrimido-[4,5-b][1,5]benzodiazepine derivatives. The structure of isomeric N-methyl-pyrazoles (X c) and (XI a) and of N-phenylpyrazole (X b) were elucidated by comparison with compounds prepared by unequivocal chemical methods. Pharmacological evaluation of some of the products showed only generic CNS depressant activity.

Intra-arterial Chemotherapy with Carboplatin (CBDCA) and Vepesid (VP16) in Primary Malignant Brain Tumours. Preliminary Findings.

SUMMARY: Twenty three patients (18 males) were followed from January 1993 to July 1996 for primary central nervous system malignancy: glioblastoma multiforme (GM) (15 patients), anaplastic astrocytoma (AA) (8 patients). Ninety one cycles (average 4 cycles per patient) of intraarterial chemotherapy (IACH) were administered. The IACH included: Carboplatin (CBP) 250 mg/m2 and Vepesid (VPI6) 150 mg/m2 infusion; both drugs in normal saline, 100 ml and 250 ml, were infused over 15 and 30 min respectively. IACH was repeated every two weeks four or six times according to response to chemotherapy. IACH was preceded by i.v. methylprednisolone 40mg and pure anti-emetic (5HT3 serotonin uptake inhibitors) and subcutaneous daily doses of G-CSF following IACH to prevent neutropenia. The whole treatment required a 24h hospital admission. The IACH was well-tolerated and toxicity (Miller's grade, WHO) included: two cases ofreversible pulmonary embolism (8.6%) three and ten days respectively after therapy (one patient had atrial fibrillation, two cases grade 2 vomiting, two grade 1 anaemia and three grade 3 thombocytopenia (13%). Response to therapy was evaluated in 21 out of 23 patients, two having not yet received at least four IACH cycles: 4 PRO (3 GM, 1 AA), 15 SD (10 GM, 5 AA) and 2 PR (AA). Seventeen patients responded to IACH (SD + RO) (74%), and the P Rs belonged to the AA group. Survival duration was from 16 + to 108 weeks. IACH with CP and VP16 warrants further studies focussing on drug dose and schedule. A prospective randomized multicentric trial evaluating radiotherapy and systemic chemotherapy plus/minus IACH is currently underway.

[Chemical and pharmaceutical research on pyran derivatives. XI. Synthesis of 2-dialkylamino-4-oxo-10-methyl-4H-naphtho[2,3b]pyrans]. / Ricerche chimiche e farmacologiche su derivati piranici. Nota XI-Sintesi di 2-dialchilammino-4-oxo-10-metil-4H-nafto[2,3-b]pirani.

Reaction of N,N-dialkylethoxycarbonylacetamides with 1-methyl-2-naphthol, in the presence of phosphorus oxychloride, gave rise to the formation of 2-dialkylamino-4-oxo-10-methyl-4H-naphtho[2,3-b] pyrans through the preliminary attack of the amide-phosphorus oxychloride reactant at the phenolic hydroxyl and cyclization at position 3 of the naphthalene moiety. However when (N-alkyl,N-phenyl)ethoxycarbonylacetamides were used in the reaction an ortho position of the N-phenyl group was involved in the cyclization and 1-alkyl-2(1'-methyl-2'-naphthoxy)-4-quinolones were achieved. Pharmacological investigation showed that some naphtho[2,3-b]pyran derivatives have neurotropic activity of the sedative, anticonvulsant and antidepressant type very similar to that shown by previously studied 1-oxo-3-dialkylamino-1H-naphtho[2,1-b]pyrans (5).

Cancer chemotherapy does not enhance MDR-associated 170 kd glycoprotein expression in normal blood mononuclear cells.

BACKGROUND: The multidrug resistance (MDR) associated 170kd glycoprotein (P170) is expressed at a low level in normal and malignant cells, but in the latter it becomes frequently overexpressed after chemotherapy. This study evaluated P170 expression in normal blood mononuclear cells after and during cancer chemotherapy. METHODS: P170 was detected by immunocytochemistry with two monoclonal antibodies (MRK-16 and JSB-1). RESULTS: P170 expression was low in all samples before, during and after chemotherapy. CONCLUSIONS: Cancer chemotherapy did not enhance P170 expression in normal peripheral blood mononuclear cells. The mechanisms enhancing P170 expression are likely to be more operative in tumor cells than in normal cells.

A phase II study of oral fluorouracil for gastrointestinal cancer.

Prolonged exposure to 5-fluorouracil (5-FU) is effective for gastrointestinal malignancy (GIM) and it is considered synergistic or additive to concurrent radiotherapy. Oral 5-FU (OF) could represent an easy therapy. The present study prospectively tested the toxicity and effectiveness of OF in GIM by means of 5-FU mannitol-coated tablets (MCT) at 275 or 225 mg/m2/day according to the patients age (65 years cut-off) for a period of 4 weeks every 7 weeks. Also the drug given over 5 days a week for 4 weeks was studied to assess OF toxicity over a time corresponding to that used in standard radiotherapy. Quality of life (LQ) was analyzed. Patients were 27 individuals (20 males), aged 43-70 years, pretreated with radiotherapy (four patients) or i.v. 5-FU-based chemotherapy (five patients), and with progressive malignancy of colorectum (six patients), stomach (five patients), pancreas (four patients) and liver (two patients). The total number of cycles was 91 and 16 patients had more than two cycles. Myelotoxicity was consistently absent; other toxicities greater than WHO grade 1 were: nausea (grade 2 in four patients), diarrhea (grade 2 in six and grade 3 in 11), palmar erithema (grade 2 in one), brown-turning skin (grade 2 in one) and CNS (grade 2 in one). Diarrhea was less frequent (p = 0.007) in gastric and in colorectal than in pancreas and liver cancer patients. In the 10 patients given the drug of 5 days a week, diarrhea was practically absent. LQ was above 90%. Fourteen patients (51%) had total arrest of disease, and 2 among 16 colorectal cancer patients had PR (12.5%). In conclusion, the MCT-OF was tolerated and as effective as the classic i.v. 5-FU at nonmyelosuppressive dose. The MCT-OF dose recommended for further studies is 275 mg/m2/day (or 225 above 65 years) for 4 weeks followed by a 2 week rest period.

Reduced lymphocyte subpopulations in patients with advanced or disseminated melanoma.

BACKGROUND: Studies have revealed many features of lymphocyte behavior in patients with malignant melanoma, but there are conflicting results. OBJECTIVE: The aim of this study was to measure with easily reproducible assays the circulating lymphocytes and other immunologic aspects in 33 patients with advanced or disseminated malignant melanoma (MM). METHODS: The following variables were measured: circulating monocytes; total lymphocytes; B (CD19) and T-cell subpopulations; CD3, CD4, and CD8, natural killer cells (anti-Leu-7+ or CD57 and anti-Leu-11+ or CD16) (cytofluorimetry); plasma levels of IgG, IgA, IgM, and IgE; complement fractions 3, 4, and 1Q; antibodies against foreign microorganisms (AaM) (adeno, herpes simplex, herpes zoster, measles, parotitis, cytomegalo, Epstein-Barr, and rubella viruses) and Toxoplasma; and cutaneous delayed hypersensitivity (CDH) to recall antigens (tetanus, diphtheria, Streptococcus, tuberculin, Proteus, Trichophyton, and Candida). We also studied 96 healthy persons, matched for age and geographic location, who were tested on the same days as the patients. RESULTS: In MM the number of total lymphocytes and subsets CD19, CD3, CD4, and CD8 was decreased from 25% to 40% (p < 0.001). The CD4/CD8 ratio increased (22%, p < 0.005) because of the relatively greater decrease of CD8. The CD57 and CD16 cells (expression of natural killer lymphocytes) were consistently reduced (30%; p < 0.002 to p < 0.003). C3 serum level was increased (30%; p < 0.001). Immunoglobulins, CDH, AaM, and all other tests were the same in the two groups. CONCLUSION: The single most important result seems to be a reduction of CD57 and CD16 cells in patients with advanced MM.

Preoperative chemoradiotherapy in cancer of the thoracic esophagus.

Surgery with or without adjuvant radiotherapy (RT) is the standard treatment of esophageal cancer. Preoperative radio- and chemotherapy (CT) have been introduced to improve prognosis. We report a phase II prospective non-randomized trial of preoperative RT (42 Gy/25) plus CT (cisplatin 20 mg/mq/day plus 5-fluorouracil 600 mg/mq/day, 1-5 weeks) for the treatment of thoracic esophageal cancer. From 1993, 50 patients were enrolled (40 men and 10 women, mean age 57 years, range 30-75 years). Squamous cell carcinoma accounted for 90% of cases; 10% were adenocarcinoma. Downstaging of the disease was obtained in 77.3% of cases; there were 13 (29.5%) complete responses (CR) and 21 (47.7%) partial responses (PR). Median survival was 28 and 25 months, respectively, for CR and partial response (PR) plus stable disease (SD) and progressive disease (PD) (P = 0.05). Progressive-free median survival was 22 and 17 months, respectively, for CR and PR + SD + PD (P = 0.08). Multimodal treatment of esophageal cancer showed promising results, although not significant, in terms of survival and disease progression for patients achieving a complete pathologic response.

Carboplatino (JM8) en el tratamiento del cáncer metastásico: estudio preliminar sobre toxicidad, tolerabilidad y eficacia / Carboplatinum (JM8) in the treatment of metastatic cancer: preliminary study over toxicity, tolerability and efficacy

Los autores han tratado 31 pacientes afectados con cáncer metastásico (13 cánceres de mama; cuatro de testículo; 14 misceláneos) y parcialmente ya tratados (17 con quimioterapia; cuatro también con radioterapia y cuatro también con hormonoterapia), con un derivado del platino, el carboplatino, solo (400 mg/m* cada 21 días) o en asociación (300 mg/m*) con otros antineoplásicos. Fueron suministrados en total 104 ciclos y la evaluación fue hecha después de por lo menos dos ciclos. En los 31 pacientes tuvimos cinco remisiones completas y siete parciales. En los 13 pacientes con cáncer de mama obtuvimos 46 porciento de remisiones parciales. Recordemos que después de dos ciclos no se evaluaron respuestas a nivel óseo. La mielosupresión fue la toxicidad más alta y frecuente (leucopenia en 54.8 porciento; plaquetopenia 9.6 porciento; anemia 22.5 porciento). La náusea y el vómito fueron bien controlados con los antieméticos usuales. Dos casos de presuntas reacciones alérgicas se resolvieron con el uso oportuno de cortisona y antihistamímicos. Dado que el carboplatino no demostró ser nefrotóxico y no necesitó de terapia hidratante, puede ser usado en pacientes ambulatorios. El estudio se encuentra aún abierto.