Tumor Platinum Concentrations Research Articles

Tumor Platinum Concentrations and Pathological Responses Following Cisplatin-Containing Chemotherapy in Gastric Cancer Patients.

There is a wide range in tumor response following preoperative chemotherapy in locally advanced gastric or gastroesophageal junction cancers. We investigated the relationship between tumor platinum levels and pathological responses in these patients. Tumor and adjacent normal tissues were retrieved. Pathological responses were assessed per standard criteria. Tissue platinum concentrations were determined with high-performance liquid chromatography mass spectrometry. Platinum distribution in tissue components was evaluated with imaging mass cytometry. Collagen content was evaluated using trichrome staining. Surgical specimens from 10 patients were available. Surgery was performed at a median time of 49days (range: 28-72) after the last cycle of chemotherapy. The mean platinum level in tumor tissue in patients with any response was significantly higher than in those with no response (893 ± 460 vs. 38.8 ± 8.8pg, P = 0.007), so was the collagen content (37.4 ± 6.8 vs. 11.5 ± 8.6%, P < 0.05). Platinum preferentially bound to collagen. Platinum was detectable in surgical specimens up to 72days after preoperative chemotherapy. Higher tumor platinum concentration correlated with improved pathological response. Collagen binding potentially explained the high interpatient variability in tumor platinum concentrations.

Superabsorbent Polymer Microspheres Prepared with Hypertonic Saline to Reduce Microsphere Expansion.

To analyze size changes of superabsorbent polymer (SAP) microspheres with the reduced expansion technique, and to evaluate pharmacological advantages of transarterial chemoembolization using cisplatin-loaded SAP microspheres with the reduced expansion technique. In an in vitro study, diluted contrast materials containing different concentrations of sodium ions were examined to expand SAP microspheres and determined the reduced expansion technique. Size distributions of cisplatin-loaded SAP microspheres were analyzed. In an in vivo study, TACE was performed using cisplatin-loaded SAP microspheres with the reduced expansion and control techniques in 18 VX2 rabbits. The degree of expansion was reduced to the greatest extent by using a mixture of non-ionic contrast material and 10% NaCl at a 4:1 ratio. The mean diameter of the reduced expansion of cisplatin-loaded SAP microspheres was 188.4μm, while that of the control expansion was 404.9μm. The plasma platinum concentrations of the reduced expansion group at 5min after TACE were significantly higher than those of the control expansion group (2.19 ± 0.77 vs. 0.75 ± 0.08μg/mL, P = .01). The tumor platinum concentrations of the reduced expansion group at 1h were significantly higher than those of the control expansion group (10.76 ± 2.57 vs. 1.57 ± 0.14μg/g, P = .044). The expanding level of SAP microspheres can be reduced by using hypertonic saline. Cisplatin-loaded SAP microspheres with the reduced expansion technique have the advantages of achieving higher cisplatin tissue concentration in TACE for liver tumors.

Tumor platinum concentrations and pathological responses following preoperative cisplatin-containing chemotherapy in gastric or gastroesophageal junction cancer patients.

76 Background: Perioperative chemotherapy plus surgical resection is a standard of care for locally advanced gastric or gastroesophageal junction (GEJ) cancers. There is a wide range in tumor response following cisplatin-containing preoperative chemotherapy. We investigated the relationship between tumor platinum levels and pathological tumor responses in gastric or GEJ cancer patients following preoperative chemotherapy. Methods: Tumor and adjacent normal tissues were retrieved. Pathological responses were assessed per standard criteria. Tissue platinum concentrations were determined with high-performance liquid chromatography mass spectrometry. Platinum distribution in tissue components was evaluated with imaging mass cytometry. Tissue collagen content was evaluated using trichrome staining. Results: Ten patients were enrolled in this study. Nine patients received 3 cycles of preoperative chemotherapy and 1 received 2 cycles. The median cumulative cisplatin dose was 166.8 mg/m2 (range: 95.9–181.1 mg/m2). Surgery was performed at a median time of 49 days (range: 28–72 days) after the last cycle of chemotherapy. The mean platinum level in tumor tissue in patients with any response was 893 ± 460 pg, significantly higher than in those with no response [38.8 ± 8.8 pg (p = 0.007)]. The collagen content was significantly higher in patients with any response than in those with no response (37.4 ± 6.8% vs. 11.5 ± 8.6%, p &lt; 0.05). Platinum preferentially bound to collagen. Conclusions: Platinum was detectable in surgical specimens up to 72 days after preoperative chemotherapy. Higher tumor platinum concentration correlated with improved pathological response. Collagen binding potentially explained the high interpatient variability in tumor platinum concentrations.

Highlights from Recent Cancer Literature

Highlights from Recent Cancer Literature

Effect of diabetes on biodistribution, nephrotoxicity and antitumor activity of cisplatin in mice

Both types of diabetes are associated with higher incidence of some types of cancer. Treating cancer in diabetic patients without aggravating diabetes-related complications is a challenge for clinicians. Additionally, little is known about how diabetes affects the treatment of cancer. One of the most effective chemotherapeutic drugs is cisplatin, which is nephrotoxic. Studies suggest that diabetes acts as a protective factor against the nephrotoxicity of cisplatin, but the mechanisms involved have not been elucidated yet. This renal protection has been attributed to decreased accumulation of cisplatin in the kidneys, which could be associated with deficient active transport of proximal tubular cells or to pharmacokinetic alterations caused by diabetes. However, it is uncertain if diabetes also compromises the antitumor activity of cisplatin. To address this issue, we developed a mouse model bearing cisplatin-induced nephrotoxicity, Sarcoma 180 and streptozotocin-induced diabetes. Four groups of treatment were defined: (i) control, (ii) diabetic, (iii) cisplatin and (iv) diabetic treated with cisplatin. The following parameters were evaluated: renal function, oxidative stress, apoptosis, renal histopathology, tumor remission, survival rate, genotoxicity and platinum concentration in tumor and several organs. Results indicate that diabetes protects against the renal damage induced by cisplatin, while also compromises its antitumor effectiveness. This is the first study to demonstrate this effect.

Effects of intratumoral administration of a hyaluronan-cisplatin nanoconjugate to five dogs with soft tissue sarcomas

To determine the effects of intratumoral injection of a hyaluronan-cisplatin nanoconjugate on local and systemic platinum concentrations and systemic toxicosis. 5 dogs with spontaneous soft tissue sarcomas (STSs). For each dog, approximately 1.5 mL of hyaluronan nanocarrier conjugated with 20 mg of cisplatin was injected into an external STS. Blood samples were collected immediately before (0 hours) and at 0.5, 1, 2, 3, 4, 24, and 96 hours after hyaluronan-cisplatin injection for pharmacokinetic analyses. Urine samples were obtained at 0 and at 96 hours after hyaluronan-cisplatin injection for urinalysis. Each treated STS and its sentinel lymph nodes were surgically removed 96 hours after the hyaluronan-cisplatin injection. Inductively coupled plasma mass spectrometry was used to measure platinum concentrations in blood samples, tumors, and lymph nodes. No tissue reactions were detected 96 hours after hyaluronan-cisplatin injection. Mean ± SD area under the curve, peak concentration, and terminal half-life for unbound (plasma) and total (serum) platinum were 774.6 ± 221.1 ng•h/mL and 3,562.1 ± 2,031.1 ng•h/mL, 56.5 ± 20.9 ng/mL and 81.6 ± 40.4 ng/mL, and 33.6 ± 16.1 hours and 51.2 ± 29.1 hours, respectively. Platinum concentrations ranged from 3,325 to 8,229 ng/g in STSs and 130 to 6,066 ng/g in STS-associated lymph nodes. Intratumoral injection of the hyaluronan-cisplatin nanoconjugate was well tolerated in treated dogs. Following intratumoral hyaluronan-cisplatin injection, platinum concentration was 1,000-fold and 100-fold greater within treated tumors and tumor-draining lymphatics, respectively, compared with that in plasma.

E10A, an adenovirus-carrying endostatin gene, dramatically increased the tumor drug concentration of metronomic chemotherapy with low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma.

Most cancer chemotherapeutic agents are administered at the maximum-tolerated dose (MTD) in short cycles with treatment breaks. However, MTD-based chemotherapies are often associated with significant toxicity and treatment breaks allow the opportunity for tumor regrowth and acquisition of chemoresistance. To minimize these drawbacks, a metronomic strategy, in which chemotherapeutics are administered at doses significantly below the MTD without treatment breaks, has been suggested by many investigators. The antitumor effect of metronomic chemotherapy may be partially due to inhibition of tumor angiogenesis, and it could be enhanced by a combination therapy, including antiangiogenic agents. In this study, we evaluated the synergistic effect of E10A, an adenovirus carrying the endostatin gene, the most potent inhibitors of tumor angiogenesis, in combination with weekly low-dose cisplatin in a xenograft mouse model for head and neck squamous-cell carcinoma. The E10A induced mRNA and protein expressions of endostatin in H891 cells in vitro. E10A significantly enhanced the in vivo tumor growth inhibitory effect of cisplatin. Immunohistochemical analysis with a TUNEL (terminal deoxynucleotidyl transferase-mediated nick-end labeling) assay and anti-CD31 antibodies revealed that the combination of E10A and cisplatin induced high levels of cell apoptosis and inhibited tumor angiogenesis. Importantly, E10A increased the platinum concentrations in tumors to fivefold higher than that induced by cisplatin alone.

Chemotherapy targeting regional lymphatic tissues to treat rabbits bearing VX2 tumor in the mammary glands

Lymph node status is one of the decisive prognostic factors in breast cancer. Chemotherapy targeting regional lymphatic tissues has emerged as a promising approach for the treatment of malignancies with high tendency to disseminate lymphatically. In this study, rabbits bearing well-developed VX2 tumors in the mammary gland received carboplatin-activated carbon suspension (CP-CH) administered subcutaneously (s.c.), carboplatin solution (CP-Sol) s.c., CP-Sol intravenously (i.v.), or a sham therapy, respectively, 6 weeks after tumor implantation. The platinum concentrations in breast tumors, axillary lymph nodes, and distant metastases were determined by Zeeman atomic absorption spectrometry (AAS). Therapeutic effects were assessed in terms of tumor and node volume ratio, cell proliferation and necrosis. Compared to CP-CH or CP-Sol s.c., CP-Sol i.v. exhibited more strong cytotoxic efficacy on breast tumor and distant metastases. In contrast, CP-CH s.c. produced much higher drug concentrations and more evident antitumor activities in axillary nodes, as demonstrated by the inhibited node growth, declined mRNA level of proliferating cell nuclear antigen (PCNA), and more extensive tumor necrosis. Based on these data, we recommend lymphatic chemotherapy to be used as an effective component of the approach to the systemic treatment on breast cancer patients with positive lymph nodes.

Effects of Irradiation Combined with Cis‐diamminedichloroplatinum (CDDP) Suppository in Rabbit VX2 Rectal Tumors

To decrease local recurrence and increase disease free survival, various preoperative therapies for patients with advanced rectal cancer have been studied. Cis-diamminedichloroplatinum (II) (CDDP) has become one of the most widely used cancer chemotherapeutic drugs. It has also been found to have radiosensitizing properties. In this experimental study, the efficacy of chemoradiotherapy using a novel CDDP suppository, and one with mixed micelles, was examined in a rabbit VX2 rectal tumor model. Rabbits were divided into four groups: control group, irradiation (R) group, CDDP suppository plus irradiation (CR) group, and mixed micelles plus CDDP suppository plus irradiation (CMR) group. Tumor growth ratios were reduced significantly in the CR and CMR groups as compared with the ratio in the control group. Microscopically, response rates of main tumors were 0%, 33.3%, 70.0%, and 91. 7%, respectively. The number of metastatic lymph nodes in the CR and CMR groups decreased significantly compared to the control group and the R group. The microscopic response rates of metastatic lymph nodes were 0%, 11.1%, 40.0%, and 41.7%, respectively. Lung metastases were observed in three rabbits in the R group, and in one rabbit in the CMR group. Tissue platinum concentrations both in tumors and in regional lymph nodes increased significantly when mixed micelles were used. Chemoradiotherapy using the CDDP suppository and mixed micelles was effective for local control in the rabbit VX2 rectal tumor model.

Digitonin enhances the antitumor effect of cisplatin during isolated lung perfusion

Background. The antitumor effect of isolated lung perfusion with cisplatin was limited because the intracellular platinum concentration did not increase sufficiently. To solve this problem, digitonin, a detergent, was chosen to increase cell permeability and enhance intracellular uptake and antitumor effect. This study was designed to investigate toxicity, pharmacokinetics, and efficacy of isolated lung perfusion with the combined use of digitonin and cisplatin in Fischer 344 rats. Methods. Systemic and local toxicities of isolated lung perfusion treatment were evaluated on the basis of body weight change, survival rate, and histologic findings. The maximal tolerated dose of digitonin was determined by assessing survival on day 21 after contralateral pneumonectomy, body weight change, and histologic findings. Pharmacokinetics were observed in a solitary lung tumor nodule model by measuring platinum concentration in tumor and normal lung tissue. The antitumor effect was evaluated by the number of tumor nodules in the left lung 21 days after isolated lung perfusion. Isolated lung perfusion was performed 7 days after 1.0 × 10 6 methylcholanthrene sarcoma cells were injected into the external jugular vein. Results. The maximal tolerated dose of digitonin was 20 μmol/L. Platinum concentration of tumor nodules in the digitonin-cisplatin–treated rats was 20% higher than in the cisplatin-only group (5.48 ± 0.64 μg/g tissue versus 4.50 ± 1.09 μg/g tissue; p = 0.067). The number of pulmonary nodules decreased significantly by digitonin use (1.3 ± 1.5 versus 9.7 ± 2; p < 0.0001). Conclusions. Isolated lung perfusion with digitonin and cisplatin in combination was performed safely and enhanced the antitumor effect. These drugs in combination show promise for enhancing the effect of clinical isolated lung perfusion.

Relationship between the concentration of CDDP in tumor and tumor size after isolated lung perfusion treatment experimental study on a solitary pulmonary sarcoma model in rats.

Few investigations on the pharmacokinetics of isolated lung perfusion (ILP) regional chemotherapy in tumors have been conducted. The purpose of this study was to evaluate the pharmacokinetic character of ILP in tumor tissues. Materials and Methods A solitary tumor nodule model was established in Fisher 344 rats by inoculating 1.0 x 10(6) methylcholanthrene-induced sarcoma cells into the left lung. On 14-21 days after the inoculation of tumor cells, rats were randomized into groups subjected to 10, 20, 40 or 60 min ILP with cis-diamminedichloroplatinum (CDDP) at concentrations of 25, 50, or 100 microg/ml. Total platinum concentration in tumors was measured by a flameless atomic absorption spectrophotometer. The average tumor weights and total platinum concentrations were not significantly different among the perfusion groups. We found, however, that the total platinum concentrations in tumor nodules were significantly correlated inversely with the tumor weight (total platinum concentration in tumor = 1.167 x 1/tumor wt; R(2) = 0.981; P < 0.001). The concentration of total platinum in the tumor tissue was found to be dependent on the weight of the tumor in ILP. Higher concentrations of total platinum were expressed in smaller tumor nodules than larger ones, indicating that ILP may be more effective against small tumors than large ones. Therefore, we suggest that large tumor legions should be debulked before ILP in patients with an unresectable lung tumor.

Pharmacological studies of cisplatin encapsulated in long-circulating liposomes in mouse tumor models.

We investigated the pharmacokinetics and therapeutic efficacy of cisplatin encapsulated in polyethyleneglycol-coated long-circulating liposomes in a formulation referred to as SPI-077, in three mouse tumor models (M-109 lung carcinoma inoculated s.c., J-6456 lymphoma inoculated i.p. and A-375 melanoma inoculated s.c.). Tumor-bearing mice were injected i.v. with single doses of SPI-077 and cisplatin. For pharmacokinetic experiments, mice were sacrificed at different timepoints post-treatment. Platinum levels were determined in plasma, spleen, liver, kidneys and tumors using flameless atomic absorption spectrophotometry. Survival times and/or tumor size were recorded for therapeutic studies. The pharmacokinetic studies revealed a prolonged circulation time and enhanced tumor uptake for SPI-077. In contrast to these results, no superior antitumor activity of SPI-077 over cisplatin could be observed in all tumor models. In vitro release experiments showed a negligible release (below 10%) of platinum from the liposomes. An in vitro cytotoxicity assay indicated a reduced cytotoxic activity of SPI-077 in comparison to cisplatin. We concluded that SPI-077 is being delivered to the tumor sites in a low bioavailability form, with extremely slow release kinetics. This explains the discrepant results of high platinum concentrations in tumors and reduced therapeutic activity after administration of SPI-077.

Contrast-enhanced MR imaging assessment of tumor capillary permeability: effect of irradiation on delivery of chemotherapy.

To assess the effect of x rays on tumor capillary permeability with macromolecular contrast medium (MMCM)-enhanced magnetic resonance (MR) imaging. One of paired R3230 mammary adenocarcinomas implanted in the flanks of 48 Fischer rats was treated with a single 5- or 15-Gy dose of x rays. After 1 or 3 days, MR imaging in 30 rats was performed unenhanced and enhanced with albumin-(gadolinium diethylenetriaminepentaacetic acid)30 (0.02 mmol gadolinium per kilogram body weight). Signal intensity enhancement was analyzed to estimate fractional blood volume and permeability-surface area product (PS). In 18 irradiated rats, 2.5 mg/kg cisplatin was injected intravenously, and fractional tumor platinum concentrations were measured spectrometrically. MR imaging showed highest capillary permeability 1 day after 15 Gy (PS 110% above control [P<.001]); PS was elevated 57% 1 day after 5 Gy and 63% 3 days after 15 Gy (P<.05). The largest mean tumor platinum fraction occurred 1 day after 15 Gy: 48% versus 20% (control)(P<.05). Transient irradiation-induced increase in tumor capillary permeability to cisplatin can be quantified with MMCM-enhanced MR imaging.

Selective intra-arterial infusion of high-dose cisplatin in patients with advanced head and neck cancer results in high tumor platinum concentrations and cisplatin-DNA adduct formation

Selective intra-arterial infusion of high-dose cisplatin in patients with advanced head and neck cancer results in high tumor platinum concentrations and cisplatin-DNA adduct formation

Selective intra-arterial infusion of high-dose cisplatin in patients with advanced head and neck cancer results in high tumor platinum concentrations and cisplatin-DNA adduct formation.

A group of 23 patients with advanced head and neck cancer were treated with highly selective intra-arterial (IA) cisplatin 150 mg/m2 delivered rapidly through microcatheters. The systemic effects of cisplatin were neutralized by concurrent administration of sodium thiosulfate. Two-to-threefold higher tumor platinum contents were detected in tumor biopsies after selective IA cisplatin administration compared to historical controls (treated with 100 mg/m2 IA). Cisplatin-induced DNA modification in human tumor biopsies was quantitated using the antiserum NKI-A59. High levels of cisplatin DNA adducts were detected which correlated linearly with the tumor platinum content (r2 = 0.62). The addition of radiotherapy to this high dose intensity cisplatin treatment resulted in a 92% complete response (CR) rate (12 of 13 patients achieved a CR). Since no difference in tumor platinum content was detected between patients receiving or not receiving radiotherapy (13 and 10 patients, respectively), but the response rate was substantially different (12 CR and 1 partial response with radiotherapy versus 6 partial and 4 non-responders without radiotherapy), these data suggest that the high platinum levels achieved by selective IA infusion were sufficient to produce enough interaction with radiotherapy to cause a 92% CR rate. Whether this interaction is additive or synergistic is as yet unclear.

Effects of intralesional injection of cisplatin dissolved in urografin and lipiodol on Ehrlich ascites tumor and normal tissues of CD-1 mice.

The response of Ehrlich ascites tumor and the effect on normal tissues (kidney and small intestine) of CD-1 mice were evaluated after intralesional (i.l.) injection of cisplatin dissolved in urografin and lipiodol, which is henceforth termed CUL suspension. The results obtained were compared with the effects of i.p. and i.l. injections of cisplatin dissolved in sterile distilled water. Each of these treatment modalities involves the injection of 10 mg/kg cisplatin. The tumor response was evaluated by tumor growth-delay studies as well as by determining the percentage of cells in the S phase. Toxicity studies were accomplished by evaluation of the change in the body weight of mice and also by S-phase studies. S-phase fraction analyses were done with the use of the Cell Proliferation Kit. This commercial kit was used to measure bromodeoxyuridine (BrdU), a thymidine analogue that is incorporated into cells synthesizing DNA. Tumor, kidney, and small-intestine platinum concentrations were determined by measurement with a flameless atomic absorption spectrophotometer. The results of the tumor growth-delay studies showed that i.p. injection, with water being the drug carrier, produced the weakest antitumor effect, whereas i.l. injection of cisplatin, with lipiodol being the drug carrier, evoked the most enhanced effect. This finding was substantiated by BrdU-uptake analysis of tumor cells, wherein i.p. injections yielded the highest S-phase fraction and CUL treatment gave the lowest. Toxicity studies showed that a very significant decrease in body weight occurred in mice receiving i.p. treatment. No significant decrease in body weight was noted after i.l. treatment. BrdU analysis revealed that DNA synthesis in kidney cells and crypt cells of the small intestine was depressed after i.p. treatment. On the other hand, no significant effect was observed in the kidney or small intestine of CUL-treated mice. A correlation between the effects of the various treatment modalities (on tumors, kidney, and small intestine) and the retention of cisplatin was found.

Cisplatin and radiation in the treatment of tumors of the central nervous system: pharmacological considerations and results of early studies

Purpose : To review the human central nervous system pharmacology of cisplatin, factors that affect cisplatin uptake in tumors, and use alone and with radiation for the treatment of primary brain tumors. Methods and Materials : The authors review their own prior published and unpublished experience and data published by other groups on the above issues. Results : Cisplatin is one of the most active chemotherapy drugs available for the treatment of solid tumors. It is synergistic with several other agents, including radiation. While it attains only low concentrations in the normal central nervous system, concentrations and plasma-tissue transfer constants for human intracerebral tumors are comparable to those in extracerebral tumors. Tumor type appears to be a more important determinant of platinum concentration than is tumor location, and gliomas do achieve lower concentrations than do other intracerebral or excracerebral tumors. Several other factors have also been identified that correlate with concentrations of cisplatin achieved in human tumors. While cisplatin alone and in combination with other drugs does have some degree of efficacy against primary brain tumors, combining it with cranial irradiation has generally not resulted in any substantial improvement in outcome to date, although some individual studies have been somewhat encouraging. New approaches are currently under investigation. Conclusion : Human pharmacology studies provide a rationale for use of cisplatin in the treatment of human brain tumors, and human and in vitro studies suggest some manipulations that might potentially further augment tumor platinum concentrations. While clinical studies suggest that cisplatin combinations may be of some value vs. human primary brain tumors and brain metastases, and while in vitro studies suggest that cisplatin potentiates radiation efficacy, no combination of cisplatin plus radiation yet tested has appeared to be superior to radiation alone.

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.

Effect of bismuth nitrate given in combination withcis-diamminedichloroplatinum(II) on the antitumor activity and renal toxicity of the latter in nude mice inoculated with human bladder tumor

The effects of bismuth nitrate pretreatment on the toxicity and antitumor activity of cis-diamminedichloroplatinum (cisplatin, CDDP) were examined in nude mice that had been inoculated with human bladder-tumor tissue. Pretreatment with bismuth nitrate depressed the renal toxicity of CDDP without compromising its activity against a transplantable human bladder tumor. Renal metallothionein (MT) and bismuth (Bi) levels in nude mice were markedly increased by Bi preadministration, but no significant MT induction was observed in inoculated human bladder-tumor tissue in which only a trace amount of Bi was incorporated. Furthermore, it was confirmed that tumor platinum (Pt) concentrations in CDDP-treated mice were not affected by Bi pretreatment. Thus, the administration of Bi compounds prior to chemotherapy with CDDP may provide an effective mode of treatment for advanced bladder tumors.

The use of oxaliplatin versus cisplatin in intraperitoneal chemotherapy in cancers restricted to the peritoneal cavity in the rat

Pharmacokinetic studies demonstrated the advantage of intraperitoneal oxaliplatin (1-OHP) for cancers restricted to the peritoneal cavity. The area under the concentration X time curve (AUC) in the peritoneal cavity for both total and ultrafiltered drug was almost 2 times higher for 1-OHP than cisplatin (cDDP). The AUC for ultrafiltered 1-OHP in plasma was also a factor 4 higher than cDDP, indicating that peritoneal tumors received a higher exposure from 1-OHP than cDDP directly in the peritoneal cavity and indirectly via the systemic circulation. Total platinum concentrations in peritoneal tumors of rats were determined after i.p. administration of equimolar doses of 1-OHP and cDDP. In spite of the pharmacological advantages, no significant difference in platinum concentration was demonstrated. In addition, no difference in the distribution of platinum within peritoneal tumors was detected after i.p. treatment with equimolar doses, i.e., platinum concentrations were comparable both in the periphery, 29 +/- 4 ppm for cDDP and 22 +/- 8 for 1-OHP and in the center of the tumor, 18 +/- 3 for both drugs. When CC531 tumor cells were incubated in vitro with equimolar concentrations of 1-DHP and cDDP in vitro, 2 to 4 times less platinum was found in cells treated with 1-OHP, indicating that the uptake of 1-OHP differed from that of cDDP. Oxaliplatin was not cross resistant for cDDP in CC531.RL4 tumor cells, a cDDP resistant cell line, which may indicate its value in ovarian cancer patients who did not respond to earlier cDDP treatment.