Surveillance of patients with differentiated thyroid cancer and indeterminate response: a longitudinal study on basal thyroglobulin trend.

PURPOSE: This is a longitudinal study of retrospective data aimed at verifying whether repeated measurements of serum non-stimulated thyroglobulin (Tg) allow the prediction of persistent disease in patients with differentiated thyroid cancer (DTC) and indeterminate response. METHODS: We examined 145 DTC patients with indeterminate response to therapy followed up for a median time of 68 months. Tg measurements and neck ultrasound (US) were performed every 6-12 months. The changes over time of repeated measurements of basal Tg were analyzed through the multilevel linear regression. RESULTS: Seventy (48.3%) out of 145 patients spontaneously achieved an excellent response, while persistent indeterminate response was observed in 62 (42.7%) patients. The remaining 13 (9.0%) patients had progression: 3/13 with biochemical disease and 10/13 with structural disease. Tg steadily increased in patients with progressive disease (mean percentage change + 27.1% at each follow-up visit), while Tg decreased in patients without any evidence of progression (mean percentage change - 8.8%). This different trend between the two groups was not related to either different values of median TSH at baseline (0.32 vs 0.28 mIU/l, respectively) or to different trend of TSH during follow-up (p = 0.76). Basal Tg values did not increase in three out of ten patients with structural disease that was identified by neck US. CONCLUSIONS: The importance of the study is that, in DTC patients with indeterminate response, rising values of unstimulated Tg, independently from the basal levels, may be useful to identify patients with progressive disease. These results are also useful to avoid unnecessary TSH stimulation.

Improved therapeutic index of cisplatin by procaine hydrochloride.

The local anesthetic procaine hydrochloride (P.HCl) had little effect on the sensitivity of P388 leukemic cells to cisplatin (DDP) in vitro, but the simultaneous administration of DDP and P.HCl (40 mg/kg) to BDF1 mice produced 50% lethal dose (LD50) and 90% lethal dose (LD90) values approximately two times higher than those observed with DDP alone. DDP-P.HCl diluted in water and administered intraperitoneally (IP) on day 1 and on days 1 and 5 to BDF1 mice bearing P388 leukemic cells produced 33% and 50% cure rates, respectively, at the maximum tolerated dose (16 mg/kg for the single administration and 10 mg/kg given on days 1 and 5). In contrast, under the same conditions, the cure rates obtained with DDP alone (10 mg/kg for the single administration and 8 mg/kg given on days 1 and 5) were 17% and 9%, respectively. Protection from DDP nephrotoxicity seems to be the explanation for the higher doses of DDP that mice can tolerate when DDP is given simultaneously with P.HCl. In fact, the increased blood urea nitrogen (BUN) levels observed 4-7 days following a single IP administration of DDP (8 or 16 mg/kg), as well as the tubular degenerative changes detected by light microscopy, were not observed when the same doses of DDP were given simultaneously with P.HCl. Since DDP nephrotoxicity is known to be reduced when the drug is diluted in 0.9% NaCl solution, we compared the combinations DDP-P.HCl in water, and DDP and DDP-P.HCl in 0.9% NaCl solution. The antitumor activity of DDP diluted in water and administered with P.HCl was similar to that observed in mice treated with DDP alone diluted in 0.9% NaCl solution. However, further improvement of the therapeutic index was achieved after the administration of DDP-P.HCl diluted in 0.9% NaCl solution; this regimen produced a cure rate of 67% (12 of 18 animals). The clinical relevance of these findings is strengthened by the observation that similar results were obtained when P.HCl was given by the intravenous route.

Regional pharmacokinetic selectivity of intrapleural cisplatin.

The pharmacokinetics and toxicity of cisplatin were investigated in 3 patients affected by malignant mesothelioma who received 90 mg/m2 of the drug intrapleurally. The mean area under the pleural Pt concentration versus time curve (AUC) [12.83 (S.D. 4.06) mg.min/ml] was about 50 times greater than that detected in plasma [0.27 (0.03) mg.min/ml], indicating a clear pharmacological advantage for this route of administration. The mean plasma total Pt concentration was 1.1 micrograms/ml and the apparent total body clearance was 268 (101) ml/min. Platinum plasma pharmacokinetic data measured following intrapleural cisplatin administration (4 patients) were compared with those observed in 7 patients treated intravenously with the same dose of cisplatin (90 mg/m2) under the same modalities of hydration. Intrapleural administration of cisplatin resulted in significantly lower plasma total partial AUC (P less than 0.05) and prolonged plasma levels of filterable Pt compared with intravenous administration. No difference between the two routes of cisplatin administration in the renal clearance (S.D.) of filterable Pt [132 (64) ml/min and 122 (39) ml/min for intravenous and intrapleural cisplatin, respectively] were observed. None of the mesothelioma patients developed clinical symptoms or signs of pleural inflammation. The intrapleural treatment did not produce haemotoxicity and the emetic toxicity was lower compared with that observed in patients receiving cisplatin intravenously.

Serial determination of platinum, protein content and free sulfhydryl levels in plasma of patients treated with cisplatin or carboplatin.

We report here the results of serial determinations of free-sulfhydryl, protein content and platinum levels in plasma of cancer patients following either cisplatin (cis-DDP, 3 patients, 60 mg/m2) or carboplatin (JM-8, 3 patients, 300 mg/m2) i.v. administration. After treatment with cis-DDP, significant platinum binding to plasma components with MW greater than 25 kD was observed; the ratio free-sulfhydryls/protein content decreased during the first two hours, returning to normal values at 24 hours after injection. In contrast, no evidence of platinum binding to plasma components with MW greater than 25 kD was noted after JM-8 i.v. administration, and the ratio free sulfhydryls/protein content did not change significantly after treatment. In vitro experiments show that at a molar ratio cis-DDP:JM-8 1:10, the two compounds bind to low MW thiols with the same kinetics. These data seems to suggest different interactions at the plasma level of these drugs, which may be correlated with their different toxicity.

Effect of normal saline on cisplatin pharmacokinetics and antitumor activity in mice bearing P388 leukemia.

The effect of normal saline (NS) on the antitumor activity, toxicity and pharmacokinetic of cisplatin (DDP) was investigated in BDF1 mice bearing P388 leukemia. Tumor-bearing mice received 8 or 16 mg/Kg of DDP dissolved in NS or distilled water (DW) intraperitoneally. Control animals were treated with DW or NS alone. The administration of 8 mg/Kg of DDP+NS produced a significantly better survival (P less than 0.05) compared to that observed in mice receiving DDP+DW. The proportion of long-term survivors was 3.5 times higher in the DDP+NS group (39%) compared to the DDP+DW group (11%). The administration of 16 mg/kg DDP+DW was highly toxic, resulting in early deaths (MST = 5 days) and no long-term survivors. NS protected from DDP toxicity without further improving the survival achieved following the injection of 8 mg/kg DDP+NS. Investigation of platinum pharmacokinetics showed that NS significantly decreases both plasma and tissue concentrations of total platinum, mainly through a decrease in the amount of platinum bound to high molecular weight plasma proteins. HPLC studies indicated that mice receiving 8 mg/kg DDP+NS or DDP+DW fail to show clear differences both in the total ultrafilterable platinum and unchanged DDP in plasma ultrafiltrate. Conversely, mice treated with DDP+NS had higher concentrations of platinum-species in plasma ultrafiltrate than mice receiving DDP+DW. These latter results, together with the observation that NS decreases the amount of platinum bound to plasma proteins, suggest that the effect of NS does not solely depend in vivo on the ability of the chloride ion concentration to stabilize the DDP molecule and suppress the formation of DDP metabolites, but also on its ability to prevent DDP toxicity by reducing the protein binding of DDP aquated products.

Synthesis and antitumor activity of a new cis-diammineplatinum (II) complex containing procaine hydrochloride.

This paper refers to some of the chemical and biological properties of a new platinum (II) complex where the aromatic amino group of procaine is involved in the coordination with platinum and whose structure was defined by UV, IR, 1H-NMR, and elemental analysis. This new cationic platinum-triamine complex (DPR) displays excellent solubility (> 50 mg/ml) and stability in water. DPR has significant in vitro cytotoxicity against murine P388 leukemic cell line, human K562 erythroleukemic cell line and human Jurkat T cell line. The in vitro cytotoxic effects of DPR on P388 and Jurkat leukemic cells were comparable to those of cis-diamminedichloroplatinum (II) (DDP), while its activity on K562 cells was significantly better than that of DDP [IC50 = 1.07 +/- 0.36 (SD) microM vs 2.62 +/- 0.23 (SD) microM, P < 0.01]. The in vitro Pt accumulation rate for P388 cells was twice as rapid after DPR than after DDP exposure, while no difference in cellular platinum efflux was observed. The antitumor activity of DPR was tested in vivo against P388 leukemic cells in BDF1 mice and gave a % ILS value (75%) similar to that of the maximum tolerated dose (MTD) of DDP (8 mg/Kg). A comparative study of plasma urea nitrogen (PUN) levels and kidney morphological analysis in tumor-bearing mice receiving the LD50 dose of both drugs (39.3 mg/Kg and 16.5 mg/Kg for DPR and DDP, respectively), showed DPR to be less nephrotoxic than DDP. These results indicate that this new cationic platinum-triamine complex containing primary amine ligand is surprisingly active both in vitro and in vivo. In summary, the good characteristics of DPR in terms of high solubility, encouraging anticancer activity and absence of nephrotoxic effects make DPR a promising new platinum anticancer agent for preclinical development.

The erbB 2 oncogene and chemotherapy: a mini-review.

The erbB 2 gene, also known as Her-2/neu, is an oncogene that encodes a transmembrane glycoprotein receptor. When overexpressed erbB 2 is an indicator of poor prognosis in a number of cancers. Recent studies show that erbB 2 expression plays a role in the prediction of responsiveness to adjuvant treatment: tumors that had an overexpression of the oncogene were less responsive to treatment than those with a normal amount. Some studies on this oncogene have examined the production of anti-erbB 2 monoclonal antibodies and evaluated the combined effect of monoclonal antibody and chemotherapeutics.

Hepatotoxicity of camptothecin derivatives in a primary culture system of rat hepatocytes.

The topoisomerase I inhibitors are a new class of antineoplastic agents currently under clinical development. Among these compounds there are some camptothecin (CPT) derivatives with improved toxicity profiles and antitumor activity: irinotecan (CPT-11) and topotecan (TPT), particularly active against colon, lung and ovarian cancer. The aim of this study was to evaluate the cytotoxicity of CPT, CPT-11, its metabolite SN38 and TPT in a primary culture system of rat hepatocytes. Cytotoxicity was evaluated by measuring the leakage of lactate dehydrogenase (LDH) into the medium and by assessing cell viability in terms of tetrazolium salts (MTT) reduction by mitochondrial dehydrogenase activity. Our results showed that cytotoxicity was limited in the case of short drug exposure. There was a significant and time-dependent increase in LDH leakage and a significant time- and dose-dependent decrease in MTT reduction after 3 h of incubation (p<0.01). In the treatments with doses related to peak plasma levels, CPT-11 was less responsible for the observed in vitro hepatotoxicity than its metabolite SN38; TPT had lower LDH leakage compared to SN38 and CPT-11 but showed significant and early (3 h) decrease in MTT reduction: this may mean a different mechanism of cellular damage. These results demonstrate that CPT derivatives are directly toxic to liver cells in a distinct time- and dose-related response.

Tumor-associated urokinase-type plasminogen activator: significance in breast cancer.

Urokinase-type plasminogen activator (u-PA), a proteolitic enzyme, capable of degrading type 4 collagen, is supposed to be involved in degradation of extracellular matrix during cancer invasion. Evidence has been presented that primary breast cancer patients with tumors containing high levels of u-PA experience a worse prognosis. u-PA and its inhibitor, type 1 plasminogen activator inhibitor (PAI-1), are potentially important prognostic factors in breast cancer to identify patients at high risk for recurrence and also in the classification of clinically important subgroups.

Prognostic significance of the estrogen-regulated proteins, cathepsin-D and pS2, in breast cancer.

The evaluation of prognostic factors for breast cancers is important for therapeutic decisions both at the time of surgery and during postoperative surveillance. Cathepsin-D (cath-D) is an estrogen inducible aspartyl protease. Studies have demonstrated two biological activities, at an acidic PH, of the protein: a mitogenic and a proteolytic activity; both the growth promoting activity and the extracellular proteolytic activity suggest that cathepsin D (cath-D) may have prognostic significance in breast cancer. Measurement of cath-D in breast tissue, in fact, is highly significant in predicting recurrence as well as disease free interval and overall survival. The pS2 is a small cysteine-rich protein specifically expressed under estrogen transcriptional control. Expression of the pS2 protein in breast carcinoma is a useful guide to prognosis and response to tamoxifen: appropriate adjuvant therapy can be selected on the pS2 status of the tumor; patients with pS2 expression had better overall survival and a longer survival time after the first recurrence than those without pS2 expression. For these reasons, these two new prognostic markers could be suggested as habit factors in breast cancer.

[pS2 protein and breast cancer]. / Proteina pS2 e carcinoma mammario.

pS2 is a small protein (7000 daltons) that is prevalently expressed in human breast cancer positive for estrogen receptors: protein is, in fact, induced by estrogen stimulation. Studies indicate that pS2 protein is a marker for hormone-dependent breast tumors and that its expression is helpful in the prognosis. The presence of pS2, in fact, besides being associated in 96% of the cases to the positivities for estrogen receptors, is associated with longer overall, and disease free, survival. The pS2 protein is also expressed in normal stomach mucosa; its physiological function is unknown.

Para-aminobenzoic acid suppression of cis-diamminedichloroplatinum(II) nephrotoxicity.

Concurrent administration of para-aminobenzoic acid (PABA) reduced the toxicity of cis-diamminedichloroplatinum(II) (DDP) in a dose-related manner in rats. When administered i.p. simultaneously with 7.5 mg/kg DDP, PABA (100 mg/kg) significantly reduced plasma urea nitrogen (PUN) and plasma creatinine levels as well as DDP-induced weight loss. Increasing doses of PABA (25, 50 and 100 mg/kg) correlated with progressively better parameters of renal activity and body wt and with lower levels of platinum in plasma and tissues in rats killed 5 days after drug administration. The formation of cisplatin-DNA adducts, the total platinum levels in kidney and testes and the DDP-induced tumor response were investigated in the presence and absence of PABA exposure in mice bearing P388 leukemic cells. Renal and testicular DNA-adducts in mice treated i.p. with 16 mg/kg DDP in normal saline were higher than those observed in mice receiving the same protocol and added PABA. Analysis of tissue platinum content demonstrated significantly lower platinum levels both in kidneys (P < 0.05) and testes (P < 0.01) of mice receiving DDP and PABA in normal saline compared to those receiving only DDP in normal saline. PABA did not affect the in vivo and in vitro antitumor activity of DDP against P388 leukemia, and there was no significant PABA-induced modification in the concentration of platinum both in the tumor cells and in DNA samples isolated from P388 leukemic cells of DDP-treated mice. We conclude that PABA may be a promising compound for reducing DDP-toxic side effects, including nephrotoxicity, without compromising its antitumor activity.

Liver and tumor uptake and plasma pharmacokinetic of arterial cisplatin administered with and without starch microspheres in patients with liver metastases.

Arterial chemoembolization of liver tumors should improve regional treatment by reducing native blood flow of the whole organ and redistributing residual flow toward hypovascular masses. Plasma cisplatin pharmacokinetics and its tissue uptake and relative tumor and liver vascularity were studied during surgical placement of arterial catheters in four patients and in four patients with colorectal metastases given intraoperative arterial cisplatin (DDP, 25 mg/m2), with an without coadministration of 600 mg degradable starch microspheres (DSM). Mean (+/- standard deviation) filterable plasma platinum levels peaked later (2 minutes) and were significantly lower after DDP with DSM (1.23 +/- 0.69 micrograms/ml) than after DDP alone (2.13 +/- 0.43 micrograms/ml, P less than 0.05), with the area under the curve (AUC0-30 min) values of 15.8 +/- 5.5 and 25.1 +/- 3.8 micrograms x min/ml (P less than 0.05), respectively. No differences in urine excretion, total body clearance, or plasma protein binding of platinum were observed. Tissue biopsies were started 15 minutes after DDP administration and completed in all cases within 5 minutes. Tumor platinum concentrations were significantly higher after DDP with DSM (3.03 +/- 1.60 micrograms/g) than after DDP alone (0.67 +/- 0.49 micrograms/ml, P less than 0.05). Liver concentrations and tumor-liver ratios of platinum also were higher, although not significantly, after DDP with DSM. Preoperative vascularization, studied with arterial perfusion scan, influenced individual tissue drug uptake in cases given DDP alone, with the lowest tumor levels in cold masses. Very high and almost superimposable liver and tumor concentrations were measured in those receiving DDP and DSM. The latter phenomenon was irrespective of native vascularization, indicating that DSM administration induced both an increased whole-liver extraction of the drug and a redistribution of blood flow and flow-dependent tissue uptake of platinum.

Regional pharmacokinetic selectivity of intraperitoneal cisplatin in ovarian cancer.

Five patients with intraabdominal ovarian cancer, 4 of whom with concomitant ascites, refractory to cisplatin-containing combination chemotherapy were treated with intraperitoneal cisplatin. Cisplatin, 90 mg/m2, was administered intraperitoneally in 2 liters of warm 0.9% NaCl with a 4-hour dwelling time on day 1 q 21 days. Platinum concentrations in plasma, ascites, ultrafiltrates of plasma and ascites, and urine were assayed by flameless atomic absorption spectrophotometry and determinations were verified by neutron activation analysis. Peak total and ultrafiltrable plasma platinum levels were 1.63 +/- 0.6 and 0.76 +/- 0.3 microgram/ml, respectively. Peritoneal clearance of total platinum (PA) was 21 ml/min whereas body clearance of total platinum was on the average 13.8 times PA, varying from 171 to 429 ml/min; the mean AUC (peritoneum) to AUC (plasma) ratio was 11 +/- 3. In 2 patients control of ascites was obtained, in 1 of these patients prior positive cytology became negative after her first intraperitoneal course. No nephrotoxicity was observed and gastrointestinal toxicity was mild. No catheter-related infections were observed. Intraperitoneal cisplatin therapy is well tolerated, pharmacokinetically rational and may be useful in managing ovarian cancer patients with malignant ascites or minimal residual disease at second-look laparotomy.