Tissue Platinum Concentrations Research Articles

In Vivo Sonoporation Effect Under the Presence of a Large Amount of Micro-Nano Bubbles in Swine Liver.

Sonoporation as a method of intracellular drug and gene delivery has not yet progressed to being used in vivo. The aim of this study was to prove the feasibility of sonoporation at a level practical for use in vivo by using a large amount of carbon dioxide micro-nano bubbles. The carbon dioxide micro-nano bubbles and 100 mg of cisplatin were intra-arterially injected to the swine livers, and ultrasound irradiation was performed from the surface of the liver under laparotomy during the intra-arterial injection. After the intra-arterial injection, ultrasound-irradiated and nonirradiated liver tissues were immediately excised. Tissue platinum concentration was measured using inductively coupled plasma mass spectrometry. Liver tissue platinum concentrations were compared between the irradiated tissue and nonirradiated tissue using the Wilcoxon signed rank test. The mean (SD) liver tissue platinum concentration was 6.260*103 (2.070) ng/g in the irradiated liver tissue and 3.280*103 (0.430) ng/g in the nonirradiated liver tissue, showing significantly higher concentrations in the irradiated tissue ( P = 0.004). In conclusion, increasing the tissue concentration of administered cisplatin in the livers of living swine through the effect of sonoporation was possible in the presence of a large amount of micro-nano bubbles.

In-vivo Sonoporation Effect Under the Presence of a Large Amount of Micro-Nano Bubbles in Swine Liver

Sonoporation as a method of intracellular drug and gene delivery has not yet progressed to being used in vivo. This is likely because the cavitation effect is too small to reach a level practical for in vivo use. The aim of this study was to prove the feasibility of sonoporation at a level practical for use in vivo by injecting a large amount of carbon dioxide micro-nanobubbles into swine livers and applying ultrasound irradiation. Nine swine placed under general anesthesia were used. The carbon dioxide micro-nanobubbles and drug were injected through a catheter into the hepatic artery. The carbon dioxide micro-nanobubbles and 100 mg of cisplatin were intraarterially injected over a period of 10 minutes, and ultrasound irradiation was performed from the surface of the liver under laparotomy during the intraarterial injection. The swine were euthanized immediately after the intraarterial injection, after which ultrasound-irradiated and non-irradiated liver tissues were immediately excised. Cross-sections of the excised liver tissue were examined with the naked eye for any abnormalities. Increased cisplatin concentration was evaluated as increased platinum concentration. Tissue platinum concentration was measured using inductively coupled plasma mass spectrometry. Liver tissue platinum concentrations were compared between the irradiated tissue and non-irradiated tissue using the Wilcoxon signed-rank test. The mean (± SD) liver tissue platinum concentration was 6.260*103 ± 2.070 ng/g in the irradiated liver tissue and 3.280*103 ± 0.430 ng/g in the non-irradiated liver tissue, showing significantly higher concentrations in the irradiated tissue than in the non-irradiated tissue (p = 0.004). No abnormal macroscopic findings were seen in the liver tissue harvested from any of the specimens. In conclusion, increasing the tissue concentration of administered cisplatin in the livers of living swine through the effect of sonoporation was possible by performing ultrasound irradiation of these livers in the presence of a large amount of micro-nanobubbles. A sonoporation effect practical for use in vivo can be achieved if a large amount of micro-nanobubbles is present.

Wide variation in tissue, systemic, and drain fluid exposure after oxaliplatin-based HIPEC: results of the GUTOX study

PurposeIn this exploratory study, the effect of postprocedural flushing with crystalloids after oxaliplatin-based hyperthermic intraperitoneal chemotherapy (HIPEC) on platinum concentrations in peritoneal tissue, blood, and drain fluid was studied. Interpatient variability in oxaliplatin pharmacokinetics and the relation between platinum concentration in peritoneal fluid and platinum exposure in tissue and blood was explored.MethodsTen patients with peritoneal carcinomatosis of colorectal origin were treated with HIPEC including postprocedural flushing, followed by ten patients without flushing afterwards. Tissue, peritoneal fluid, blood, and drain fluid samples were collected for measurement of total and ultrafiltered platinum concentrations.ResultsPeritoneal tissue concentration and systemic ultrafiltered platinum exposure showed large inter individual variability, ranging from 65 to 1640 µg/g dry weight and 10.5 to 28.0 µg*h/ml, respectively. No effect of flushing was found on geometric mean platinum concentration in peritoneal tissue (348 vs. 356 µg/g dry weight), blood (14.8 vs. 18.1 µg*h/ml), or drain fluid (day 1: 7.6 vs. 7.7 µg/ml; day 2: 1.7 vs. 1.9 µg/ml). The platinum concentration in peritoneal fluid at the start of HIPEC differed twofold between patients and was positively correlated with systemic exposure (p = .04) and peak plasma concentration (p = .04).ConclusionIn this exploratory study, no effect was found for postprocedural flushing on platinum concentrations in peritoneal tissue, blood, or drain fluid. BSA-based HIPEC procedure leads to large interpatient variability in platinum exposure in all compartments.The study was registered at ClinicalTrials.gov on 7 December 2017 under registration number NCT03364907.

Quantitative evaluation of the intratumoral distribution of platinum in oxaliplatin-treated rectal cancer: In situ visualization of platinum via synchrotron radiation X-ray fluorescence spectrometry.

Oxaliplatin (l-OHP), a platinum-based drug, is a key chemotherapeutic agent for colorectal cancer (CRC), but drug resistance and toxic effects have been major limitations of its use. Synchrotron radiation X-ray fluorescence spectrometry (SR-XRF) is a rapid, nondestructive technique for monitoring the distribution of metals and trace elements in cells or tissue samples. We applied SR-XRF to visualize the distribution of platinum and other elements in 30 rectal cancer specimens resected from patients who received l-OHP-based preoperative chemotherapy and quantified platinum concentration in the tumor epithelium and stroma, respectively, using calibration curves. The platinum concentration in rectal cancer tissue ranged 2.85-11.44 ppm, and the detection limit of platinum was 1.848 ppm. In the tumor epithelium, the platinum concentration was significantly higher in areas of degeneration caused by chemotherapy than in nondegenerated area (p < 0.001). Conversely, in the tumor stroma, the platinum concentration was significantly higher in patients with limited therapeutic responses than in those with strong therapeutic responses (p < 0.001). Furthermore, multivariate analysis illustrated that higher platinum concentration in the tumor stroma was an independent predictive factor of limited histologic response (odds ratio; 19.99, 95% confidence interval; 2.04-196.37, p = 0.013). This is the first study to visualize and quantify the distribution of platinum in human cancer tissues using SR-XRF. These results suggest that SR-XRF analysis may contribute to predicting the therapeutic effect of l-OHP-based chemotherapy by quantifying the distribution of platinum.

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.

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.

Pharmacodynamics of Oxaliplatin-Derived Platinum Compounds During Hyperthermic Intraperitoneal Chemotherapy (HIPEC): An Emerging Aspect Supporting the Rational Design of Treatment Protocols.

Hyperthermic intraperitoneal chemotherapy (HIPEC) is used to treat peritoneal surface malignancies with application of cytostatic drugs such as oxaliplatin (OX) after cytoreductive surgery. Despite its increased use, evidence for optimal drug dosage, and notably duration of HIPEC, is scarce. In this study, OX distribution was comprehensively assessed in nine patients during HIPEC (300 mg OX/m2 body surface area in Physioneal solution for 30 min). Oxaliplatin and its derivatives were measured in peritoneal perfusates over time by liquid chromatography coupled with mass spectrometry (LC-MS), and the resulting total platinum concentration in tissue was analyzed by atomic absorption spectrometry. Additionally, a novel impedance-based real-time cytotoxicity assay was used to evaluate the bioactivity of perfusates ex vivo. Compared with amounts of OX expected in peritoneal perfusates by calculation, only 10-15% of the parent drug could be detected by LC-MS during HIPEC. Notably, the study additionally detected platinum compounds consistent with OX transformation, accounting for a further fraction of the applied drug. The cytotoxic properties of perfusates remained unchanged during HIPEC, with only a slight but significant attenuation evidenced after 30 min. The bioactivity of peritoneal perfusates ex vivo is a useful parameter for evaluating the actual cytotoxic potential of OX and its derivatives used in HIPEC over time, overcoming important limitations and disadvantages associated with respective drug monitoring only. Ex vivo cytotoxicity assays may be a promising tool to aid guiding future standardization and harmonization of HIPEC protocols based on drug-mediated effects.

Platinum concentration in bladder tissue treated with neoadjuvant chemotherapy and pathologic response.

341 Background: Platinum (Pt) resistance is a major limitation in the treatment of muscle-invasive bladder cancer (MIBC), for which Pt-based chemotherapy remains the standard of care. Reduced intratumoral drug accumulation is an important mechanism of platinum resistance. Our previous studies in lung cancer demonstrate significant correlation between tissue Pt concentration and tumor response to neoadjuvant chemotherapy (NAC). Tissue Pt concentration was measured in bladder specimens exposed to Pt-based NAC and correlated to pathologic response. Methods: A cohort of 19 clinically annotated, archived frozen bladder specimens from MIBC patients treated with three to four cycles of Pt-based NAC was identified [pT0 (pathologic complete response, pCR), n=4; pTis or pT1 (pathologic partial response, pPR), n=6; &gt;/= pT2 (minimal pathologic response/progression), n=9]. Two cystectomy specimens from MIBC patients treated with Pt-based adjuvant therapy were used as controls. Non-tumor bearing adjacent bladder tissue (“normal”) was identified in cystectomy specimens by a genitourinary pathologist. Total Pt concentration in normal tissue was measured by flameless atomic absorption spectrophotometry. Three group Kruskal-Wallis tests were used to compare the distributions of Pt concentrations by pathologic response (pCR, pPR, minimal response/progression). Mann-Whitney non-parametric two-sided tests were used for two group comparisons. Results: Total Pt concentration in normal adjacent bladder tissue differed by tumor pathologic response (p=0.011). Specimens with a pCR had the highest Pt concentrations compared to those with a pPR (p=0.0095) or no response/progression (p=0.0196). There was no significant difference in Pt levels between PR and no response/progression group (p=0.37). Conclusions: Our findings suggest that enhanced Pt accumulation may be an important determinant of Pt sensitivity. Studies investigating factors that modulate intracellular Pt concentration, such as expression of influx/efflux Pt transporters, may serve as predictive biomarkers and promote increased use of Pt-based NAC.

Radiofrequency ablation combined with chemolipiodolization in a porcine liver: Comparison of the pharmacokinetic analysis with cisplatin powder and miriplatin.

To compare the pharmacokinetics of radiofrequency (RF) ablation with chemolipiodolization using cisplatin (CDDP) powder and miriplatin (MPT) in a porcine liver. Twelve pigs were divided equally into four groups. After each CDDP powder-lipiodol suspension (n = 6; groups A and B) or MPT-lipiodol suspension (n = 6; groups C and D) was injected into the lateral left artery, one RF ablation was performed at the lateral left lobe of each pig. Six pigs (groups A and C) were killed on the same day as treatment, whereas the other pigs (groups B and D) were killed 7 days after the treatment. The platinum concentrations in venous blood were assayed at 15, 60 and 120 min, and 7 days after treatment. The platinum concentrations in the ablated area and the surrounding liver were also examined. Plasma platinum concentrations of the CDDP group peaked at 15 min, and then gradually diminished over time (μg units), while plasma platinum levels in the MPT group gradually increased over time (ng units). Liver tissue platinum concentrations of the CDDP group were significantly lower in non-ablative areas than in ablated areas at days 0 and 7, while liver concentrations of the MPT group were significantly higher in non-ablative areas than in ablated areas at day 7. MPT may be a suitable chemotherapeutic agent to stagnate platinum in the surrounding liver.

Copper transporter CTR1 expression and tissue platinum concentration in non-small cell lung cancer

BackgroundPlatinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue platinum concentration in NSCLC specimens was significantly associated with reduced tumor response. Furthermore, low expression of the copper transporter CTR1, a transporter of platinum uptake was associated with poor clinical outcome following platinum-based therapy in NSCLC patients. We investigated the relationship between tissue platinum concentrations and CTR1 expression in NSCLC specimens. MethodsWe identified paraffin-embedded NSCLC tissue blocks of known tissue platinum concentrations from 30 patients who underwent neoadjuvant platinum-based chemotherapy at MD Anderson Cancer Center. Expression of CTR1 in tumors and normal adjacent lung specimens was determined by immunohistochemistry with adequate controls. ResultsTissue platinum concentration significantly correlated with tumor response in 30 patients who received neoadjuvant platinum-based chemotherapy (P<0.001). CTR1 was differentially expressed in NSCLC tumors. A subset of patients with undetectable CTR1 expression in their tumors had reduced platinum concentrations (P=0.058) and tumor response (P=0.016) compared to those with any level of CTR1 expression. We also observed that African Americans had significantly reduced CTR1 expression scores (P=0.001), tissue platinum concentrations (P=0.009) and tumor shrinkage (P=0.016) compared to Caucasians. ConclusionsTo our best knowledge this is the first study investigating the function of CTR1 in clinical specimens. CTR1 expression may be necessary for therapeutic efficacy of platinum drugs, consistent with previous preclinical studies. A prospective clinical trial is necessary to develop CTR1 into a potential biomarker for platinum drugs.

Radiofrequency Ablation After Arterial Injection of Miriplatin–Iodized Oil Suspension Into Swine Liver: Ablative Zone Size and Tissue Platinum Concentration

To evaluate whether arterial injection of miriplatin-iodized oil suspension facilitates ablative zone expansion by radiofrequency (RF) ablation using a Cool-Tip electrode and to provide effective tissue platinum concentration in the normal swine liver. RF ablation was performed at three sites of each liver. RF ablation alone was performed in two animals (control). Ablation was performed after arterial injection of iodized oil (iodized-oil group) or a miriplatin-iodized oil suspension (miriplatin group) in two animals each. Long- and short-axis diameters of the ablative zone were measured. In the miriplatin group, tissue platinum concentrations were measured in the ablative, surrounding hyperemic rim, and nonablative zones. The mean long- and short-axis diameters of ablative zones were 27.0 ± 3.1 and 18.0 ± 0.6 mm in the control. Although the long-axis diameter (30.2 ± 2.8 mm, p = 0.07) showed no significant expansion, the short-axis diameter (20.8 ± 2.6 mm, p = 0.04) was significantly expanded more in the iodized-oil group than in the control. Ablative zone sizes were largest in the miriplatin group. The long-axis diameter (33.5 ± 2.4 mm, p = 0.01) was significantly larger than that in the control. The short-axis diameter (27.2 ± 1.9 mm, p = 0.004) was significantly larger than that of the iodized-oil group. Tissue platinum concentrations showed an effective antitumor effect (≥9 μg/g) in ablative (16.5 ± 5.7 μg/g), surrounding hyperemic rim (18.0 ± 5.1 μg/g), and nonablative zones (mean 22.2 ± 5.7 μg/g) (p = 0.21). Arterial injection of miriplatin-iodized oil suspension can expand the ablative zone size and provide effective tissue platinum concentration on tumor control in the ablative zones and their surrounding hyperemic rim.

Intra-arterial infusion of thrombin: Animal experiments

Purpose: Thrombin inhibits cadherin on vascular endothelial cells, rapidly and reversibly increasing endothelial permeability. The purpose of this study was to evaluate the feasibility of trans-arterial infusion with thrombin. Material and methods: Ten rabbits with right thigh tumor were randomly divided into two groups: A thrombin group and a control group. In the thrombin group, a suspension of thrombin (300 IU), cisplatin (3 mg), lipiodol (0.3 ml) and iopamidol (0.3 ml) was infused into the right femoral artery. In the control group, a suspension of cisplatin, lipiodol and iopamidol was infused. Platinum concentrations in plasma were measured five and ten minutes after administration. Platinum concentrations were also measured in tumor specimens excised 30 minutes after infusion. Results: At both five and ten minutes after infusion, platinum concentrations in plasma were significantly lower for the thrombin group than for the control group. Platinum concentration in tumor tissue was significantly higher for the thrombin group than for the control group. Conclusion: The present results suggest that transarterial infusion with thrombin may offer a number of pharmacological advantages.

Antitumor effect of miriplatin-lipiodol suspension/emulsion using a VX2 liver tumor model

To evaluate the antitumor effects of miriplatin-lipidol suspension and emulsion. Fifty rabbits with VX2 liver tumors were randomly assigned to ten groups. Then, we prepared four types of mixtures: a suspension of lipiodol and miriplatin (ML), an emulsion of miriplatin dissolved with lipiodol and contrast medium (MLC) or saline (MLS), and saline alone (S). Ratios between lipiodol and contrast medium/saline volumes were 1:1/4, 1:1/2, 1:1, and 1:2 respectively. We used the same dose of miriplatin (2 mg/kg) and lipiodol (0.1 ml/kg) in each emulsion and suspension group. After intra-arterial infusion, the tumor growth rate was calculated, and sequential change of the plasma platinum concentration, the platinum concentration in the tumor and in surrounding normal liver tissue was also measured. Among the ten groups, the tumor growth rate was lower in MLC and MLS groups, and the difference between tumor treated with MLS emulsion (ratio 1:1/2) and ML suspension was significant (p = 0.02). The platinum concentration in the normal liver tissue was lower in MLS and MLC groups than in the ML group, and that in the tumor was higher in the MLS and MLC emulsion (ratio 1:1/2) groups. We suggest that miriplatin-lipiodol emulsion may be more effective than suspension.

Copper transporter CTR1 expression and tissue platinum concentration in NSCLC.

2601 Background: Platinum (Pt) resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue Pt concentration in NSCLC tumor specimens was significantly associated with reduced tumor response and worse survival. Furthermore, low expression of the copper transporter CTR1, a transporter of Pt uptake is reported to be associated with poor clinical outcome following Pt-based therapy in NSCLC patients. However, a defect in CTR1expression as a causative factor in reduced Pt accumulation in NSCLC tissues is not well-established. We investigated the relationship between tissue Pt concentrations and CTR1 expression in NSCLC specimens. Methods: We identified paraffin-embedded NSCLC tissue blocks from 30 patients who underwent neoadjuvant Pt-based chemotherapy with known tissue Pt concentrations at MD Anderson Cancer Center. Expression of CTR1 was determined by immunohistochemistry with adequate controls; 0 = undetectable; 1+ = barely detectable staining; 2+ = readily appreciable staining; and 3+ = dark brown staining. Pt concentration was compared between different CTR1 expression groups. Results: Tissue Pt concentration significantly correlated with tumor response in 30 patients who received neoadjuvant Pt-based chemotherapy (P&lt;0.001). There was an uneven distribution of CTR1 expression scores with a majority of specimens demonstrating scores of 2+ (N=15, 50%). There were 2 specimens with no detectable CTR1 expression (score of 0) and 6 patients with a score of 3+. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentrations compared to those with scores of 3+ (P=0.014). Furthermore, those with undetectable CTR1 expression had reduced tumor response compared to those with scores of 3+ following Pt-based chemotherapy (P=0.039). Conclusions: To the best of our knowledge, this is the first study to correlate CTR1 expression in clinical specimens to both tumor Pt uptake and response. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentration and reduced tumor response. Further evaluation with a larger sample size is required. (Supported by 2012 ASCO Young Investigator Award)

1:30 PM Abstract No. 81 - Radiofrequency ablation following arterial injection of miriplatin-iodized-oil suspension; evaluation of ablative zone size and tissue platinum concentration in the swine liver

Purpose To evaluate whether radiofrequency (RF) ablation following arterial injection of miriplatin-iodized-oil suspension expands ablative zone size, providing tissue platinum concentration with antitumor activity in the swine liver. Materials and Methods A total of 6 swine (mean weight, 49.3+/-1.7kg; weight range, 48.2-52.7 kg) underwent liver RF ablation. RF ablation alone was done in 2 animals (control), following arterial injection of iodized-oil (iodized-oil group) or miriplatin-iodized-oil suspension (miriplatin group) in 2 animals each. Ablative zones were created in 3 sites of each animal (total of 18 RF applications). Both the long- and short-axis diameters of ablative zones were measured. In the miriplatin group, tissue platinum concentrations were measured both in central and surrounding zones that were defined as white and red zones, respectively. Results The long- and short-axis diameters of the white zone were 27.0+/-3.1 mm and 18.0+/-0.6 mm in the control. Although significant expansion of long-axis diameter was not found in the iodized-oil group (30.2+/-2.8mm, p=0.09), it was significantly larger in the miliplatin group (33.5+/-2.4mm, p=0.02) than that in the control. The short-axis diameter was significantly expanded in the iodized-oil group (20.8+/-2.6mm, p=0.03) than that in the control, and it was significantly larger in the miriplatin group (27.2+/-1.9mm) than that in the iodized-oil group (p=0.001). Tissue platinum concentration reached effective antitumor activity levels both in white (16.5+/-5.8μg/g) and red zones (18.0+/-5.1μg/g). Conclusion RF ablation following arterial injection of miriplatin-iodized-oil suspension expands ablative zone size, providing tissue platinum concentration with antitumor activity.

Tissue Platinum Concentration and Tumor Response in Non–Small-Cell Lung Cancer

Platinum resistance is a major limitation in the treatment of advanced non-small-cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed the effects of tissue platinum concentrations on response and survival in NSCLC. We measured total platinum concentrations by flameless atomic absorption spectrophotometry in 44 archived fresh-frozen NSCLC specimens from patients who underwent surgical resection after neoadjuvant platinum-based chemotherapy. Tissue platinum concentration was correlated with percent reduction in tumor size on post- versus prechemotherapy computed tomography scans. The relationship between tissue platinum concentration and survival was assessed by univariate and multicovariate Cox proportional hazards regression model analysis and Kaplan-Meier analysis. Tissue platinum concentration correlated significantly with percent reduction in tumor size (P < .001). The same correlations were seen with cisplatin, carboplatin, and all histology subgroups. Furthermore, there was no significant impact of potential variables such as number of cycles and time lapse from last chemotherapy on platinum concentration. Patients with higher platinum concentration had longer time to recurrence (P = .034), progression-free survival (P = .018), and overall survival (P = .005) in the multicovariate Cox model analysis after adjusting for number of cycles. This clinical study established a relationship between tissue platinum concentration and response in NSCLC. It suggests that reduced platinum accumulation might be an important mechanism of platinum resistance in the clinical setting. Further studies investigating factors that modulate intracellular platinum concentration are warranted.

Abstract A21: Tissue platinum concentration and tumor response in non-small cell lung cancer

Abstract Background: Platinum resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). Reduced intracellular drug accumulation is one of the most consistently identified features of platinum-resistant cell lines, but clinical data are limited. We assessed effects of tissue platinum concentrations on tumor response, time to recurrence, progression-free survival (PFS) and overall survival (OS) in patients with early-stage NSCLC following neoadjuvant platinum-based chemotherapy. Methods: We measured total platinum concentrations in 44 archived fresh frozen NSCLC specimens from patients who received neoadjuvant platinum-based chemotherapy. Samples were analyzed by flameless atomic absorption spectrophotometry to assess absorbance reading associated with platinum concentration. Four specimens from patients who underwent surgery only and one patient who received pemetrexed as neoadjuvant chemotherapy were analyzed as negative controls. Absorbance value per mg of tissue was correlated with percent reduction in tumor size on post- vs prechemotherapy CT scans. Kaplan-Meier curves and log-rank tests were used to evaluate differences in time to recurrence and survival between two groups divided by median platinum concentration. Results: Platinum absorbance values in 44 neoadjuvant specimens were easily detectable and ranged from 0.6 to 6.7 × 10−3 per mg of tissue while five negative controls demonstrated absorbance readings similar to 0.1N HCL. Platinum absorbance correlated significantly with percent reduction in tumor size (R2 = 0.48, P&amp;lt;0.00001). The same correlations were seen in cisplatin (P = 0.0003), carboplatin (P = 0.0013), adenocarcinoma (P = 0.0003) and squamous cell carcinoma (P = 0.019) groups. Furthermore, there was no significant impact of potential variables such as the type of platinum compound, number of cycles, pre-treatment tumor diameter and time lapse from last chemotherapy on platinum concentration. Patients with lower Pt concentration also had shorter time to recurrence (P = 0.0494), progression free survival (P = 0.0366) and overall survival (P = 0.035). Conclusion: This is the first tissue-based study to establish a relationship between tissue platinum concentrations and response in NSCLC. Reduced intratumoral platinum accumulation may constitute a significant mechanism of platinum resistance even in clinical specimens. Further studies investigating factors that modulate intracellular platinum concentration are warranted (Supported by National Foundation of Cancer Research 90088436, Department of Defense W81XWH-07-1-0306, National Institute of Health CA127263, CA160687 and CA16672).

Pharmacologic Advantages of Negative-Balance Isolated Pelvic Perfusion: Achievement of Intensive Exposure of the Pelvis to Platinum without Systemic Leakage

To study tissue platinum concentrations and the correlation between tissue and plasma platinum concentrations after negative-balance isolated pelvic perfusion (NIPP) in a porcine model. All animal experiments were conducted according to the University Guidelines for Animal Care and Experimentation. Cisplatin (5 mg per kilogram of body weight) was administered into balloon catheter-isolated porcine pelvic circulations (n=7) and also systemically to a control group (n=7). Platinum concentrations in pelvic blood, systemic blood, urine, pelvic tissues (uterus, bladder, lymph nodes, and muscles), and kidneys were measured. Maximum platinum concentration (maximum serum drug concentration [C-max]) and area under the blood concentration-time curve (AUC) were compared between the two groups. With NIPP, pelvic C-max (58.4 mg/L) and AUC (1163.6 mg⋅min/L) were 44.9- and 56.2-fold higher than systemic C-max (1.3 mg/L) and AUC (20.7 mg⋅min/L), respectively, whereas the corresponding values in the control group were almost identical. Tissue platinum concentrations in pelvic organs were 2.8-5.6-fold higher than the control values. Platinum concentrations in kidney tissue were markedly lower with NIPP (1.0 mg/L) compared with the controls (8.1 mg/L). High platinum concentrations in pelvic tissues correlated well (P<.01) with high pelvic C-max and AUC. The pharmacologic advantages of NIPP were evident, with achievement of high platinum C-max, AUC, and high pelvic tissue concentrations without exposing systemic organs to platinum.

Cisplatin tumor biodistribution and efficacy after intratumoral injection of a biodegradable extended release implant.

Local delivery of chemotherapeutic drugs has long been recognized as a potential method for reaching high drug doses at the target site while minimizing systemic exposure. Cisplatin is one of the most effective chemotherapeutic agents for the treatment of various tumors; however, its systemic toxicity remains the primary dose-limiting factor. Here we report that incorporation of cisplatin into a fatty acid-based polymer carrier followed by a local injection into the solid tumor resulted in a successful tumor growth inhibition in heterotopic mouse bladder tumor model in mice. Platinum concentration in the tumor tissue surrounding the injected implant remained above the therapeutic level up to 14 days after the injection, while the plasma levels were several orders of magnitude lower comparing to systemic delivery. The reported delivery system increased the maximum tolerated dose of cisplatin 5 times compared to systemic delivery, thus potentially improving antitumor efficacy of cisplatin in solid tumor model.

Intra-hepatic arterial administration with miriplatin suspended in an oily lymphographic agent inhibits the growth of tumors implanted in rat livers by inducing platinum-DNA adducts to form and massive apoptosis

BackgroundMiriplatin (formerly SM-11355), a novel lipophilic platinum complex developed to treat hepatocellular carcinoma, is administered into the hepatic artery using an oily lymphographic agent (Lipiodol Ultra-Fluide®) as a carrier. We clarified the usefulness of miriplatin as an agent for transarterial chemoembolization.MethodsPlatinum compounds released from miriplatin into serum, medium and Earle’s balanced salt solution were examined. Then, miriplatin and cisplatin were administered to rats bearing hepatoma AH109A tumors in livers. Platinum concentrations in tissues and DNA were assessed.ResultsMiriplatin showed a more sustained release than cisplatin. Dichloro[(1R, 2R)-1, 2-cyclohexane diamine-N, N′]platinum, the most abundant platinum compound released from miriplatin, was as effective as cisplatin in inhibiting the growth of cells. Miriplatin was selectively disposed of in tumors, maintained in tumors longer than cisplatin and caused apparent tumor regression inducing platinum-DNA adducts to form and massive apoptosis.ConclusionMiriplatin appears to be a suitable chemotherapeutic agent for transarterial chemoembolization.