Search

Paclitaxel has been considered to cause OATP1B-mediated drug-drug interactions at therapeutic doses; however, its clinical relevance has not been demonstrated. This study aimed to elucidate in vivo inhibition potency of paclitaxel against OATP1B1 and OATP1B3 using endogenous OATP1B biomarkers. Paclitaxel is an inhibitor of OATP1B1 and OATP1B3, with Kiof 0.579 ± 0.107 and 5.29 ± 3.87 μM, respectively. Preincubation potentiated its inhibitory effect on both OATP1B1 and OATP1B3, with Kiof 0.154 ± 0.031 and 0.624 ± 0.183 μM, respectively. Ten patients with non–small cell lung cancer who received 200 mg/m2of paclitaxel by a 3-hour infusion were recruited. Plasma concentrations of 10 endogenous OATP1B biomarkers—namely, coproporphyrin I, coproporphyrin III, glycochenodeoxycholate-3-sulfate, glycochenodeoxycholate-3-glucuronide, glycodeoxycholate-3-sulfate, glycodeoxycholate-3-glucuronide, lithocholate-3-sulfate, glycolithocholate-3-sulfate, taurolithocholate-3-sulfate, and chenodeoxycholate-24-glucuronide—were determined in the patients with non–small cell lung cancer on the day before paclitaxel administration and after the end of paclitaxel infusion for 7 hours. Paclitaxel increased the area under the plasma concentration-time curve (AUC) of the endogenous biomarkers 2- to 4-fold, although a few patients did not show any increment in the AUC ratios of lithocholate-3-sulfate, glycolithocholate-3-sulfate, and taurolithocholate-3-sulfate. Therapeutic doses of paclitaxel for the treatment of non–small cell lung cancer (200 mg/m2) will cause significant OATP1B1 inhibition during and at the end of the infusion. This is the first demonstration that endogenous OATP1B biomarkers could serve as surrogate biomarkers in patients.

Pazopanib is an orally active tyrosine kinase inhibitor that exhibits hepatotoxicity in some patients. Despite the clinical importance of its hepatic distribution, the transporter(s) responsible for hepatic uptake of pazopanib in humans remain undetermined. To characterize its hepatic uptake mechanism, we screened the effects of several transporter inhibitors, including tetrapentylammonium (TPeA) for organic cation transporters (OCTs) and cyclosporin A (CsA) for organic anion-transporting polypeptides (OATPs), on both plasma disappearance and hepatic distribution of pazopanib in mice after its i.v. administration. Among the inhibitors, TPeA largely reduced hepatic distribution and plasma clearance of pazopanib, whereas CsA showed only partial reduction. Pazopanib uptake by isolated mouse hepatocytes was similarly reduced by these inhibitors, suggesting that OCTs play a major role in the overall hepatic uptake of pazopanib in mice. In human embryonic kidney cell line HEK293 cells stably transfected with human OCT1, pazopanib uptake was significantly higher than that in vector-transfected cells. Moreover, pazopanib uptake by OCT1 became saturated and was inhibited by TPeA, but not by CsA, confirming that pazopanib is also a substrate of human OCT1. Importantly, OCT1-mediated uptake of a typical OCT1 substrate metformin was inhibited by pazopanib with an IC50value of 0.253 µM, indicating that pazopanib has the potential for clinically relevant inhibition of human OCT1. Finally, pazopanib was taken up by cryopreserved human pooled hepatocytes in a time-dependent manner, and this uptake was largely reduced by TPeA but only partially reduced by CsA. Thus, the present findings suggest that OCT1 is responsible for hepatocellular uptake of pazopanib.

Weekly administration of solvent-based paclitaxel is one of the standard second-line chemotherapy regimens for advanced gastric cancer. Nanoparticle albumin-bound paclitaxel (nab-paclitaxel) was developed to improve the solubility of paclitaxel and does not need premedication to avoid infusion-related reactions associated with solvent-based paclitaxel. Additionally, higher doses of nab-paclitaxel can be administered over a shorter infusion time and at higher drug concentrations compared with solvent-based paclitaxel. We aimed to investigate the efficacy and safety of nab-paclitaxel versus solvent-based paclitaxel in patients with previously treated advanced gastric cancer.

A number of molecularly targeted anticancer drugs that efficiently inhibit receptor tyrosine kinases, socalled receptor tyrosine kinase inhibitors (TKIs), have been developed. Although these receptor TKIs are generally well tolerated, unexpected toxicities sometimes occur in various organs. TKI-induced adverse events not only lower the quality of life of cancer patients but also reduce dose intensity, and sometimes result in treatment discontinuation. To reduce adverse drug events and increase treatment efficacy, oncologists and clinical pharmacologists have made efforts to establish strategies to treat patients via optimal selection and dosing of TKIs. Drug efficacy and safety are generally determined by the interplay of multiple processes that regulate pharmacokinetics and pharmacodynamics (toxicodynamics). In this review article, we first provide an overview of adverse events caused by receptor TKIs, focusing on gefitinib, erlotinib, sorafenib and sunitinib, followed by a discussion on the association between pharmacokinetics and toxicities induced by these TKIs, with a focus on establishing optimal personalized treatment strategies by controlling pharmacokinetic properties. Finally, we introduce new findings on the molecular mechanisms of TKIinduced toxicities, elucidated using a new strategy, systems toxicology.

A number of molecularly targeted anticancer drugs that efficiently inhibit receptor tyrosine kinases, socalled receptor tyrosine kinase inhibitors (TKIs), have been developed. Although these receptor TKIs are generally well tolerated, unexpected toxicities sometimes occur in various organs. TKI-induced adverse events not only lower the quality of life of cancer patients but also reduce dose intensity, and sometimes result in treatment discontinuation. To reduce adverse drug events and increase treatment efficacy, oncologists and clinical pharmacologists have made efforts to establish strategies to treat patients via optimal selection and dosing of TKIs. Drug efficacy and safety are generally determined by the interplay of multiple processes that regulate pharmacokinetics and pharmacodynamics (toxicodynamics). In this review article, we first provide an overview of adverse events caused by receptor TKIs, focusing on gefitinib, erlotinib, sorafenib and sunitinib, followed by a discussion on the association between pharmacokinetics and toxicities induced by these TKIs, with a focus on establishing optimal personalized treatment strategies by controlling pharmacokinetic properties. Finally, we introduce new findings on the molecular mechanisms of TKIinduced toxicities, elucidated using a new strategy, systems toxicology.

Cytotoxic anticancer drugs are the most challenging therapeutic agents among all medicines with relatively narrow efficacy profiles. Therefore, medical oncologists have to practically manage the risk of severe toxic effects to optimize treatment outcomes. Dose and treatment-schedule recommendations for cytotoxic anticancer agents are determined on the basis of clinical trials. Patients enrolled in clinical trials are those likely to receive the drug in clinical practice, excluding those with conditions such as organ dysfunction, obesity, advanced age, or comorbidity. On the other hand, the ‘real world’ includes large numbers of such patients who do not meet the eligibility criteria of clinical trials. However, there is a paucity of data from sufficiently powered pharmacokinetic and pharmacodynamic studies to support dosage recommendations in such patients. Consequently, dose levels and treatment schedules for chemotherapy in these subjects are somewhat arbitrary and not evidence-based. Pharmacokinetic and pharmacodynamic studies of patients in the ‘real world’ are needed to address this issue. In this review article, we describe general aspects of clinical pharmacology in cancer patients enrolled in clinical trials and those in the ‘real world,’ and introduce recent findings regarding the pharmacokinetic and pharmacodynamic properties of irinotecan and S-1 in ‘real world’ cancer patients.

[123I]N-Isopropyl-p-iodoamphetamine hydrochloride ([123I]IMP) is clinically used to evaluate blood flow in the brain on single photon emission-computed tomography. This is a rare radiopharmaceutical that undergoes metabolism. The first step is reported to be [123I]p-iodoamphetamine formation. The drug-metabolizing enzyme(s) involved remain(s) unclear. This study examined the roles of human cytochrome P450 (P450) in the metabolism of nonradiolabeled IMP with the use of human liver microsomes (HLM) and recombinant human CYP1A1, -1A2, -1B1, -2A6, -2B6, -2C8, -2C9, -2C19, -2D6, -2E1, -3A4, and -3A5. Disappearance of IMP was examined because p-iodoamphetamine was not available. IMP (0.5 μM) time-dependently disappeared when HLM and NADPH-generating system were added to the reaction mixture. (S)-Mephenytoin (1 mM) inhibited the IMP disappearance by approximately 90%. The disappearance of IMP was predominantly catalyzed by recombinant CYP2C19, with Kmand Vmaxof 8.6 μM and 9.7 nmol · min−1· nmol P450−1, respectively. IMP disappearance in CYP2C19-deficient HLM (CYP2C19*2/*2) was approximately 30% of that in the presence of HLM harboring wild-type CYP2C19, indicating that IMP is polymorphically metabolized by CYP2C19. High-performance liquid chromatography of the incubation mixture of IMP and CYP2C19 revealed an unidentified peak. As the area of the IMP peak decreased, the area of this unidentified peak increased in a time-dependent fashion. The peak was also detectable on incubation of IMP with HLM. Mass spectrometry revealed that the molecular weight of a compound in this unidentified peak was the same as that of p-iodoamphetamine. Thus, we demonstrated that IMP was predominantly metabolized by CYP2C19 to form p-iodoamphetamine.

[123I]N-Isopropyl-p-iodoamphetamine hydrochloride ([123I]IMP) is clinically used to evaluate blood flow in the brain on single photon emission-computed tomography. This is a rare radiopharmaceutical that undergoes metabolism. The first step is reported to be [123I]p-iodoamphetamine formation. The drug-metabolizing enzyme(s) involved remain(s) unclear. This study examined the roles of human cytochrome P450 (P450) in the metabolism of nonradiolabeled IMP with the use of human liver microsomes (HLM) and recombinant human CYP1A1, -1A2, -1B1, -2A6, -2B6, -2C8, -2C9, -2C19, -2D6, -2E1, -3A4, and -3A5. Disappearance of IMP was examined because p-iodoamphetamine was not available. IMP (0.5 μM) time-dependently disappeared when HLM and NADPH-generating system were added to the reaction mixture. (S)-Mephenytoin (1 mM) inhibited the IMP disappearance by approximately 90%. The disappearance of IMP was predominantly catalyzed by recombinant CYP2C19, with Kmand Vmaxof 8.6 μM and 9.7 nmol · min–1· nmol P450–1, respectively. IMP disappearance in CYP2C19-deficient HLM (CYP2C19*2/*2) was approximately 30% of that in the presence of HLM harboring wild-type CYP2C19, indicating that IMP is polymorphically metabolized by CYP2C19. High-performance liquid chromatography of the incubation mixture of IMP and CYP2C19 revealed an unidentified peak. As the area of the IMP peak decreased, the area of this unidentified peak increased in a time-dependent fashion. The peak was also detectable on incubation of IMP with HLM. Mass spectrometry revealed that the molecular weight of a compound in this unidentified peak was the same as that of p-iodoamphetamine. Thus, we demonstrated that IMP was predominantly metabolized by CYP2C19 to form p-iodoamphetamine.

This exploratory retrospective study examined the effects of polymorphisms in transporter genes related to irinotecan pharmacokinetics and those in genes related to irinotecan pharmacodynamics on the efficacy of first-line combination chemotherapy with irinotecan, 5-fluorouracil, and folinic acid (leucovorin) (FOLFIRI) in Japanese patients with advanced colorectal cancer. All patients harbored UDP-glucuronosyltransferase (UGT) 1A1 *1/*1, *1/*6,or *1/*28genotypes, which are associated with similar irinotecan pharmacokinetics and responses to FOLFIRI. Genetic polymorphisms were analyzed by direct sequencing. Overall response rate and median progression-free survival in a total of 61 patients were 43% and 7.5 months, respectively. The overall response rate was higher in patients with the CC genotype at –24 in ATP-binding cassette, subfamily C, and member 2 (ABCC2)than in the others (p = 0.0313). Median progression-free survival was the longest in patients with CC at –24 in ABCC2,followed by those with CT and TT (p = 0.00910). A clear gene-dose effect was seen between –24C>T and median progression-free survival. No other polymorphisms tested were related to the efficacy of FOLFIRI. We thus found that the –24C>T polymorphism in the ABCC2gene was significantly associated with the efficacy of first-line FOLFIRI in Japanese patients with advanced colorectal cancer.

Sorafenib and sunitinib are novel small-molecule molecularly targeted anticancer drugs that inhibit multiple tyrosine kinases. These medicines have shown survival benefits in advanced renal cell carcinomas as well as in advanced hepatocellular carcinomas and gastrointestinal stromal tumors, respectively. The effects of sorafenib and sunitinib on midazolam 1'-hydroxylation catalyzed by human CYP3A4 or CYP3A5 were investigated. Sorafenib and sunitinib inhibited metabolic reactions catalyzed by recombinant CYP3A4. Midazolam hydroxylation was also inhibited in human liver microsomes harboring the CYP3A5*3/*3 genotype (poor CYP3A5 expressor). In contrast, midazolam 1'-hydroxylation catalyzed by recombinant CYP3A5 was enhanced by the coexistence of sorafenib or sunitinib in a concentration-dependent manner, with saturation occurring at approximately 10 µM. Midazolam hydroxylation was also enhanced in human liver microsomal samples harboring the CYP3A5*1/*1 genotype (extensive CYP3A5 expressor). Sorafenib N-oxidation and sunitinib N-deethylation, the primary routes of metabolism, were predominantly catalyzed by CYP3A4 but not by CYP3A5. The preincubation period of sorafenib and sunitinib before the midazolam addition in the reaction mixture did not affect the enhancement of CYP3A5-catalyzed midazolam hydroxylation, indicating that the enhancement was caused by parent sorafenib and sunitinib. Docking studies with a CYP3A5 homology model based on the structure of CYP3A4 revealed that midazolam closely docked to the heme of CYP3A5 compared with sorafenib or sunitinib, suggesting that these anticancer drugs act as enhancers, not as substrates. Our results thus showed that sorafenib and sunitinib activated midazolam 1'-hydroxylation by CYP3A5 but inhibited that by CYP3A4. Unexpected drug interactions involving sorafenib and sunitinib might occur via heterotropic cooperativity of CYP3A5.

This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤20 ml/min] who were undergoing dialysis and received 100 mg/m2irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr ≥60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase(UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28were enrolled. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P= 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m2dialysis membrane, whereas 27% was dialyzed with a 1.5-m2membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.

This prospective study is designed to examine the effects of severe renal failure on the pharmacokinetics of irinotecan. The pharmacokinetics of irinotecan, 7-ethyl-10-hydroxycamptothecin (SN-38), and SN-38 glucuronide (SN-38G) in three cancer patients with severe renal failure [creatinine clearance (Ccr) ≤20 ml/min] who were undergoing dialysis and received 100 mg/m2irinotecan as monotherapy were prospectively compared with those in five cancer patients with normal renal function (Ccr ≥60 ml/min). To ensure that the subjects had similar genetic backgrounds of UDP-glucuronosyltransferase (UGT) 1A1, patients with UGT1A1*1/*1, *1/*6, or *1/*28 were enrolled. The estimated terminal elimination rate constant of SN-38 in patients undergoing dialysis was approximately one tenth of that in patients with normal renal function (P = 0.025). Approximately 50% of SN-38 was dialyzed with a 2.1-m2dialysis membrane, whereas 27% was dialyzed with a 1.5-m2membrane. Our results showed that the elimination of SN-38 was significantly delayed in patients with severe renal failure compared with patients with normal renal function. We demonstrated that SN-38 was partly dialyzed.

Cancer chemotherapy is characterized by a broad range of efficacy and toxicity among patients. Most anticancer drugs show wide interindividual variability in pharmacokinetics and have narrow therapeutic windows. Since drug metabolism is often an essential determinant of interindividual variability in pharmacokinetics, pharmacogenomic studies of drug-metabolizing enzymes are expected to rationalize cancer chemotherapy in terms of patient, treatment, and dosage selection. Candidate gene approaches to pharmacogenomics are based on existing knowledge in clinical pharmacology, used to select the target(s) to be analyzed. So far, the candidate gene approach has provided important clues for pharmacogenomic-based personalized chemotherapy with 6-mercaptopurine (6-MP), solely metabolized by thiopurine S-methyltransferase (TPMT), and irinotecan, mainly detoxified by UDP-glucuronosyltransferase 1A1 (UGT1A1). Reduced activity of TPMT caused by polymorphisms in the TPMT gene and decreased activity of UGT1A1 caused by UGT1A1*28 are related to severe toxic effects of 6-MP and irinotecan, respectively. In response to these findings, the Food and Drug Administration in the United States has supported clinical pharmacogenetic testing by revising the package inserts for these anticancer drugs. The genome wide approach to pharmacogenomics has gradually evolved with continued progress in genome sciences and technologies. This approach can disclose previously unknown relations of factors, as well as identify potential multigenetic associations. The genome wide approach can also identify genes underlying the phenotypic effects of anticancer drugs. This approach may play a complemental role to the candidate gene approach in the future of cancer pharmacogenomics. This review describes recent progress in pharmacogenomics in the field of cancer chemotherapy.

We sequenced exon 1 of the UDP-glucuronosyltransferase (UGT) 1A7gene from 52 Japanese cancer patients. Four single nucleotide polymorphisms (SNPs) were found. Three of them caused UGT1A7*2and UGT1A7*3. A novel SNP (98973G>C) causing amino acid substitution (Ser141Cys) was found. The sequence is as follows: SNP, 050824FujitaK002; GENE NAME, UGT1A7; ACCESSION NUMBER, AF297093; LENGTH, 25 bases; 5′-TAAAGGAGAGTTGWCTTTTGATGC-AGT-3′. One out of 52 cancer patients was heterozygous for the variant allele, resulting in the allele frequency of 0.96%. The patient did not possess UGT1A7*2or UGT1A7*3.

Gefitinib (Iressa) is an anticancer drug that selectively inhibits tyrosine kinases of epidermal growth factor receptor. Gefitinib might affect CYP3A4-mediated metabolism, since the drug is a substrate of human CYP3A. In this study, we evaluated the effects of gefitinib on drug metabolism catalyzed by human CYP3A4. The effects of gefitinib on the CYP3A4-mediated formation of NPC (7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin) and that of APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin) from irinotecan were examined with the use of human liver and small intestinal microsomes. Gefitinib inhibited the formation of NPC in liver and small intestinal microsomes. The apparent intrinsic metabolic clearance (CLint) in the presence of 40 μM gefitinib was equivalent to about 26% of control in liver microsomes and 45% of control in small intestinal microsomes. Gefitinib stimulated the formation of APC by CYP3A4. CLintin the presence of 20 μM gefitinib with human liver microsomes was about 1.9 times higher than control. In human small intestinal microsomes, APC formation was enhanced by the addition of gefitinib at concentrations 20 μM or higher. CLintin the presence of 40 μM gefitinib was 2.8 times higher than control. Thus, we discovered that gefitinib inhibited the formation of NPC but stimulated the formation of APC from irinotecan.

Gefitinib (Iressa) is an anticancer drug that selectively inhibits tyrosine kinases of epidermal growth factor receptor. Gefitinib might affect CYP3A4-mediated metabolism, since the drug is a substrate of human CYP3A. In this study, we evaluated the effects of gefitinib on drug metabolism catalyzed by human CYP3A4. The effects of gefitinib on the CYP3A4-mediated formation of NPC (7-ethyl-10-(4-amino-1-piperidino)carbonyloxycamptothecin) and that of APC (7-ethyl-10-[4-N-(5-aminopentanoic acid)-1-piperidino]carbonyloxycamptothecin) from irinotecan were examined with the use of human liver and small intestinal microsomes. Gefitinib inhibited the formation of NPC in liver and small intestinal microsomes. The apparent intrinsic metabolic clearance (CLint) in the presence of 40 µM gefitinib was equivalent to about 26% of control in liver microsomes and 45% of control in small intestinal microsomes. Gefitinib stimulated the formation of APC by CYP3A4. CLint in the presence of 20 µM gefitinib with human liver microsomes was about 1.9 times higher than control. In human small intestinal microsomes, APC formation was enhanced by the addition of gefitinib at concentrations 20 µM or higher. CLint in the presence of 40 µM gefitinib was 2.8 times higher than control. Thus, we discovered that gefitinib inhibited the formation of NPC but stimulated the formation of APC from irinotecan.

The purpose of this study was to investigate the treatable subsets in cancer of unknown primary origin (CUP). Fifty patients (27 males and 23 females; median age, 53 years) with CUP diagnosed between April 1992 and June 1999 were analyzed retrospectively. Of the 50 patients, 39 received chemotherapy: platinum‐based in 31, non‐platinum‐based in 4, and clinical trials of new agents in 4. Of the 39 patients, 13 (33.3%; 95% confidence interval: 19.1–50.2%) showed objective responses, with 4 complete responders. Patients with poorly differentiated carcinomas in whom p‐subunit of human chorionic gonadotropin (β‐HCG) was elevated more than 10 mlU/ml and female patients with peritoneal adenocarcinomatosis achieved high response rates (83.3% and 80%, respectively) with platinum‐based chemotherapy, as compared with only a 15.3% response rate in the remaining patients. Platinum‐based chemotherapy provided promising results in patients with poorly differentiated carcinomas and in female patients with peritoneal adenocarcinomatosis. Significantly elevated serum levels of β‐HCG in patients with poorly differentiated carcinoma might predict a better response to platinum‐based chemotherapy. However, the investigation of novel chemotherapeutic approaches is warranted for other groups of patients with CUP.

The entire time course of leukopenia after anticancer treatment is clinically more relevant than a singly measured nadir count. In order to identify factors associated with neutropenic fever, a mechanistic pharmacodynamic model with two compartments corresponding to leukocytes in bone marrow and peripheral blood was applied to describe the time course of leukopenia. Seventeen patients with breast cancer were treated with 210 mg/m2of paclitaxel infused over 3 h as a single agent in a phase II study. Adequate fitting of the time course of leukopenia was achieved in all patients, and time‐dependent parameters, including the tune period during which leukocyte counts remained below 2000/μl and the area between the curve for time versus leukocyte counts and the line of a leukocyte count of 2000/μl (A<2000), were calculated in each patient. Leukopenia was not significantly correlated with pharmacokinetic parameters, including time above a threshold concentration or the area under the tune‐concentration curve. A negative correlation between age and the sensitivity parameter of the pharmacodynamic model was observed (r2=0.21, P=0.07). Patients who experienced neutropenic fever had a larger A<2000 than patients who did not experience fever (4512 vs. 6 days/μl, P=0.05), but fever was not significantly related to any pharmacokinetic parameter or the leukocyte nadir count. Febrile episodes were better associated with the time course of leukopenia than the singly measured nadir count, and the pharmacodynamic model presents a novel platform to analyze the entire tune course of leukopenia.

PSC‐833 reverses multidrug resistance by P‐glycoprotein at concentrations <1000 ng/ml. A phase I study of PSC‐833 and doxorubicin was conducted to determine the maximum tolerated dose and to investigate pharmacokinetics. PSC‐833 was intravenously infused as a 2‐h loading dose (LD) and a subsequent 24‐h continuous dose (CD). Doxorubicin was infused over 5 min, 1 h after the LD. The starting dose was 1 mg/kg for both LD and CD with 30 mg/m2doxorubicin; these dosages were increased to 2 and 10 mg/kg and 50 mg/m2, respectively. Thirty‐one patients were treated. Nausea/ vomiting was controllable with granisetron and dexamethasone. Neutropenia and ataxia were dose limiting. Steady‐state concentrations of PSC‐833 >1000 ng/ml were achieved at a 2 mg/kg LD and a 10 mg/kg CD. Ex‐vivobioassay revealed that activity in serum for reversing multidrug resistance was achieved in all patients; IC50of P‐glycoprotein expressing 8226/Dox6; in patients’ serum was decreased from 5.9 to 1.3 μg/ml (P<0.0001) by PSC‐833 administration. Doxorubicin clearance was 24.3±13.7 (mean±SD) liter/h/m2, which was lower than the 49.0±16.9 liter/h/m2without PSC‐833 (P<0.0001). The relationship between doxorubicin exposure and neutropenia did not differ between patients treated and not treated with PSC‐833. The recommended phase II dose of PSC‐833 was 2 and 10 mg/kg for LD and CD, respectively, which achieved a sufficient concentration in serum to reverse drug resistance, as confirmed by bioassay. The dose of doxorubicin should be reduced to 40 mg/m2, not because of the pharmacodynamic interaction between PSC‐833 and doxorubicin affecting hematopoiesis, but because of pharmacokinetic interaction.

This study was conducted to describe the relationshipbetween pharmacokinetics of CPT-11 and its active metaboliteSN-38, and clinical values with special emphasis on theinfluence of relative weight referring to the appropriatenessof a conventional dose adjustment method by body surface area(BSA). Thirty-six patients received 100 mg/m2ofCPT-11 intravenously over 90 min. Body Mass Index (BMI) wasused as a measure of relative weight which is calculated fromthe equation: BMI=weight(kg)/[height(m)]2. Thearea under the concentration-time curve (AUC) of CPT-11 wassignificantly correlated with sex, age, poorer creatinineclearance and indocyanine green retention test (ICG). Thepeak plasma concentration (Cmax) of CPT-11 was significantlycorrelated with sex a larger BMI, BSA and age. The AUC ofSN-38 was significantly correlated with ICG. The volume ofdistribution at steady state of CPT-11 inversely correlatedwith BMI. Multiple regression analysis revealed that the bestfitting model with significant independent predictors for AUCof CPT-11 included age and sex (F=6.93, R2=0.29).That of Cmax of CPT-11 included sex and BMI (F=8.96,R2=0.35). The only independent predictor of AUC ofSN-38 was ICG (F=7.75, R2=0.19). These resultsindicated that several factors affect pharmacologicalbehaviors of CPT-11 even in patients with normal organfunctions. The dose modification method based solely on BSA isnot sufficient to reduce interpatient variability of cancerchemotherapy. The influence of relative weight, sex and age onpharmacokinetics/pharmacodynamics should be taken intoconsideration in every pharmacological approach to establishthe ideal dose modification method.

Background:The optimum dose of granulocyte colony-stimulating factor (G-CSF) for peripheral blood stem cell (PBSC) mobilization after disease-oriented, conventional-dose chemotherapy remains unknown.Methods:A multicenter dose-finding study of glycosylated G-CSF (lenograstim) for the mobilization of PBSCs following adjuvant CAF chemotherapy (cyclophosphamide, doxorubicin and 5-fluorouracil) was performed in 38 patients with postoperative breast cancer. Each 10, ten and eight patients were sequentially allocated to one of the three dose groups (2,5 and 10 µg/kg, respectively) of lenograstim. Lenograstim was administered subcutaneously (s.c.) daily from day 8 to the day of the last apheresis and CD34+ cells and colony-forming units—granulocyte macrophage (CFU-GMs) in peripheral blood were measured serially. Additionally, 10 patients who received adjuvant CAF chemotherapy alone also participated in the study, as a control.Results:Lenograstim was well tolerated up to 10 µg/kg, except for one patient given 10 µg/kg who developed transient grade 3 hepatic enzyme elevation. The peak levels of CD34+ cells and CFU-GMs in peripheral blood showed dose—response relationships. The median peak CD34+ cells for the 0,2,5 and 10 Ég/kg dose groups were 5.4,34.3, 55.0 and 127.6 cells/Él, respectively, and those of CFU-GMs for the 0, 2, 5 and 10 Ég/kg dose groups were 0.01, 0.33,1.32 and 3.30 CFU-GMs/Él, respectively.Conclusions:Considering the previous reports suggesting that a pre-apheresis number of 40–50 CD34+ cells/µl in peripheral blood is highly predictive for achievement of more than 2.5 × 106CD34+ cells/kg in a standard apheresis procedure of 10 litres, the optimum dose of lenograstim for PBSC mobilization following CAF chemotherapy in patients with postoperative breast cancer is 5 µg/kg/day s.c.

Background: Because both the nadir count and the duration of leukopenia after chemotherapy with anti-cancer drugs are important, a pharmacodynamic model describing the entire time course of leukopenia is valuable. In this study, a pharmacodynamic model was developed to simulate leukopenia.Methods: The model was developed with the 3-hour infusion data of paclitaxel. A concentration-time curve of paclitaxel for each patient estimated by a 3-compartment pharmacokinetic model was used as input to the model, which had 2 compartments corresponding to leukocytes in bone marrow and peripheral blood, respectively. Differentiation stages of myeloid cells sensitive to anticancer drugs were assumed, and exposure to a drug during their sensitive period as a function of time was used to inhibit the production of leukocytes in bone marrow. The model was validated by fitting the data of 24-hour infusion of paclitaxel or 14-day infusion of etoposide.Results: Successful fitting of the leukopenia after a 3-hour infusion of paclitaxel was achieved. The following parameters were estimated: lag-time, 58 ± 38 (mean ± SD) hours before the leukocyte count started to decline; exposure giving 50% inhibition of leukocyte production (IC), 12.1 ± 6.1 μg · h/mL; and sensitive period, 288 ± 64 hours. These estimations were within physiologic ranges. In validation, leukopenia after 24-hour infusion of paclitaxel or 14-day infusion of etoposide was also explained by the model. Age was significantly negatively correlated with IC of paclitaxel (P = .039).Conclusions: This mechanistic model describes the time course of leukopenia and may provide a platform for pharmacodynamic analysis of anticancer drugs.

This report describes a rare case of roentgenographically occult small-cell lung cancer in a 73-year-old man with hemoptysis. Fiberoptic bronchoscopy disclosed a 5-mm dome-shaped lesion; a biopsy established the diagnosis of small-cell lung cancer. The patient received a combination of chemotherapy and radiotherapy. More than 10 years later, he is still alive without recurrent disease. A review of the literature of roentgenographically occult small-cell lung cancer revealed the following: (1) a history of heavy smoking was common; (2) double primary bronchogenic carcinoma was noted; (3) hemoptysis or bloody sputum was an initial common symptom; (4) the sensitivity of sputum cytologic analysis was relatively low; (5) the tumor, which was shiny, smooth, and covered with bronchial epithelium, was often located at the bifurcation; and (6) lymph node metastatic involvement occurred.

A 42-year-old female with a mediastinal tumor and massive pleural effusion was admitted to our hospital in June 1993. Biopsy revealed lymphoblastic lymphoma. She had no evidence of distant metastasis except pleural effusion. Bone marrow examination revealed a normal karyotype (46, XY). The patient had been progression-free for more than 1 year after achieving complete remission by induction, consolidation and maintenance therapy according to the standard chemotherapy and involved-field radiation for lymphoblastic lymphoma. From May 1996 progressive leukopenia and thrombocytopenia developed. The diagnosis of refractory anemia with excess of blasts (RAEB) was made. Subsequently, in November 1996, she developed acute myelogenous leukemia (AML), M4 type by FAB classification. The karyotype of MDS and AML clones involved inversion (3) (q21 q26) and monosomy 7. The EV11 gene was examined and was proved to be rearranged and activated. This may be the first case among the therapy-related cases of MDS/AML reported whose karyotypes were followed and in which the mRNA expression of EVI1 gene involved was directly proved in the leukemogenesis process of chemotherapy-in-duced secondary MDS and AML.

Background:Irinotecan (CPT-11) is a topoisomerase I inhibitor that has been confirmed to be active against a broad spectrum of neoplasms including non-Hodgkin's lymphoma (NHL). Because the combination of topoisomerase I and II inhibitors seemed to be an attractive therapeutic strategy owing to their complementary functions, we conducted a combination phase I study of CPT-11 and etoposide, a topoisomerase II inhibitor, in relapsed or refractory non-Hodgkin's lymphoma (NHL).Methods:The starting doses of CPT-11 and etoposide were 30 mg/m2/day (days 1–3 and 8–10) and 40 mg/m2(days 1–3), respectively.Results:All three patients who received the starting dose developed dose-limiting toxicities including one case of grade 4 neutropenia lasting for >7 days, one of grade 3 serum transaminase elevation and one of grade 3 hyperbilirubinemia. All three patients presented hepatotoxicity ≥grade 2. The starting dose level was judged to be the maximum tolerated dose (MTD) and further dose escalation of this combination was halted. The patient who developed grade 3 hyperbilirubinemia presented a second peak of plasma SN-38, an active metabolite of CPT-11, on the concentration-time curve for day 3, suggesting the possibility of the enterohepatic circulation of SN-38 and of a drug-to-drug interaction. No durable objective response was observed in the three patients treated at the starting dose.Conclusions:We conclude that etoposide is not recommended for combination with CPT-11 in NHL patients because of unexpected frequent hepatotoxicities.

We report the successful treatment with nedaplatin of two cases of ovarian cancer that recurred after platinum-containing chemotherapy. A 52-year-old woman presented in June 1994 with massive accumulation of ascitic fluid. Pathological diagnosis of the specimen obtained at surgery in July 1994 was serous papillary adenocarcinoma of the ovary. In September 1995, approximately seven months after the completion of six cycles of CAP chemotherapy (cyclophosphamide, adriamycin and cisplatinum), she was referred to our hospital because of massive accumulation of ascitic fluid. The carbohydrate antigen 125 (CA-125) value was 485 U/ml. Cytologic study of her ascitic fluid was positive for adenocarcinoma cells. She did not respond to intravenous irinotecan and two cycles of intraperitoneal cisplatin. Nedaplatin 100 mg/m2was administered. Complete response was achieved in September 1996 and continued for four months with a total of seven cycles of nedaplatin. The second case was a 60-year-old woman who was admitted to our hospital in December 1994 because of ascitic fluid. Diagnosis of ovarian cancer was based on an elevated level of CA-125 (1380 U/ml). Treatment with CAP and CC (cyclophosphamide and carboplatin) maintained a partial response for seven months. In August 1996, her disease progressed, although she was receiving CC therapy. Nedaplatin 100 mg/m2was administered. Partial response was achieved again in November 1996 and continued for four months, with a total of five cycles of nedaplatin. In the light of our experience, treatment with nedaplatin in a patient with recurrent ovarian cancer might be worthwhile as palliative chemotherapy.

To evaluate the efficacy and toxicity of high-dose epirubicin (EPI) plus cyclophosphamide (CPA) therapy, a phase II study of EPI, 130 mg/m2, plus CPA, 1000 mg/m2, with G-CSF every 3 weeks was carried out for 51 advanced or recurrent breast cancer patients by the Japan Clinical Oncology Group (JCOG). Fifty out of the 51 patients who were eligible for our criteria were treated with this regimen as first-line chemotherapy for visceral metastases or hormone-independent tumors. In this trial, 203 cycles were administered with an average of four cycles per patient. In 50 patients who were evaluable for response, there were 7 complete (CR) and 25 partial responses (PR) with an overall response rate of 64% (95% confidence interval, 50.1–75.9%). Symptomatic and hematological acute toxicity more than grade 3 occurred frequently; however, no treatment-related death occurred. The incidence of toxicities (≥grade 3) was as follows: leukopenia 98%, thrombocytopenia 42%, nausea/vomiting 56% and hair loss 12%. In each cycle, daily administration of 2 µg/kg G-CSF (granulocyte-colony stimulating factor) was given on days 2–15 subcutaneously. The incidence of cardiotoxicity was low. Arrhythmia (≤grade 2) was observed in 8% and a slight decrease of ejection fraction index (≤grade 2) was observed in 2% in this trial. The median follow-up period for patients was 37.2 (24.6–51.5) months and the median survival period was 17.4 months. These data indicate that high-dose EPI + CPA combination chemotherapy was effective and well tolerated for breast cancer patients with visceral metastases or hormone-independent tumors. A randomized trial of high-dose EPI vs conventional chemotherapy is required to ascertain the usefulness of this regimen.

We determined cytosol c-erbB-2 protein levels using a sandwich enzyme immunoassay in benign breast disease and primary and recurrent breast cancer and analyzed the relationship between c-erbB-2 protein levels and clinicopathological factors. Overexpression of c-erbB-2 protein, the cut-off value being set at 18 ng/mg protein, was observed in 26 of the 139 cases if stages I–IIIB breast cancer (18.7%), four of the 12 cases of stage IV breast cancer (33.3%) and seven of the 13 recurrent breast cancer cases (53.8%). The levels of c-erbB-2 protein were significantly different between the stages. Overexpression of c-erbB-2 protein in stages I–IIIB breast cancer was associated with histological grade and serum CEA level, but not with other clinicopathological factors. In addition, there was an inverse correlation in the group of stages I–III plus IV breast cancer between c-erbB-2 protein expression and estrogen receptor status. Overexpression of c-erbB-2 protein can be easily determined in the cytosol fraction together with hormonal receptor by this method. The prognostic importance will be evaluated in ongoing adjuvant trials for operable breast cancer patients.

Patients with testicular germ cell tumors who have disease-free remission for more than 2 years are usually considered to be cured of their disease. This report describes a case of a germ cell tumor recurring 12 years after initial diagnosis and its treatment in a 35-year-old man who developed a retroperitoneal mass adhering to the abdominal aorta with a bout of severe colic in the left flank. Although tumor markers were not elevated and histology of the biopsy specimen was initially diagnosed as adenocarcinoma, we finally concluded that the retroperitoneal tumor was teratoma developing as a recurrence of the germ cell tumor for the following reasons: (1) the histology of the specimen was similar to an epithelial component of teratoma found in the tissue resected 12 years before; (2) systemic survey failed to detect any other primary site; (3) the young age of this patient was consistent with germ cell tumor rather than adenocarcinoma; and (4) the retroperitoneum is the most frequent site of late recurrences of testicular cancer. He was treated successfully with combination chemotherapy of cisplatin, etoposide and bleomycin followed by surgery. It is important to differentiate this treatable disease from metastasis from an unknown primary, because the latter responds poorly to therapy and survival is usually short.

Primary Hodgkin's disease in the bone is extremely rare. We report the case of a 41-year-old woman with Hodgkin's disease, who had complained of left coxalgia 17 months prior to nodal involvement becoming evident clinically. She received combination chemotherapy with doxorubicin, bleomycin, vincristine and dacarbazine as well as radiotherapy to the pelvic lesion. Although the lymphadenopathy responded well to this treatment, the bone lesion was never in remission. The large mass of the bone lesion and its pelvic origin may explain the poor response to the cytotoxic therapies this patient received. The 22 cases reviewed showed that: 1, bony pain was the most frequent initial symptom; 2, nodal disease appeared in their clinical course in most cases; 3, the bones most commonly involved were pelvis, femur or tibia, and spine.

Abstract: The present study was conducted to compare the pharmacokinetics (PK) of low-dose versus high-dose medroxyprogesterone (MPA) as a once-daily oral administration. Of 32 patients, all women, enrolled in this PK study, 18 received 600 mg MPA daily and 14 received 1200 mg daily. Detailed PK data were obtained on day 1 and after more than 4 weeks of MPA treatment. In addition, multiple data for the minimum steady-state concentration (Css min) were analyzed. The MPA serum concentrations were measured by high-performance liquid chromatography. Wide interpatient variability was found in the PK parameters obtained both on day 1 and after more than 4 weeks. There were no clear relationships between the oral dose and the MPA peak concentration (Cmax), area under the time versus concentration curve (AUC), or mean Css min. Weight gains of 10% or more were demonstrated more frequently in the high-dose group (P<0.01). Liver dysfunction (n=5) did not influence the PK of MPA. Five patients demonstrated extremely low AUC and Cmax (<10 ng/ml) values on day 1. Phenobarbital, dexamethasone and betamethasone were being taken concomitantly with the MPA each by one patient. The serum MPA concentrations were markedly increased after the discontinuation of phenobarbital in that patient, suggesting a drug interaction. At present we cannot recommend the high dose of MPA, except in clinical studies, from a PK or a pharmacodynamic points of view.

A linear two-compartment Bayesian pharmacokinetic model was developed using a standard two-stage population method for the novel anti-cancer agent CPT-11 from 11 adult patients with refractory cancer. The accuracy and efficiency of this Bayesian model for estimating pharmacokinetic parameters including the area under the concentration-time curve (AUC) was then evaluated using two different sampling strategies in a new study cohort of 13 patients with cancer. Sampling strategies included either one, two, or three nonsteady-state feedback levels determined empirically and from optimal sampling theory (D-optimality). All 24 patients in this study received CPT-11 (60 mg/m2) as a 90-min infusion. Pharmacokinetic parameters derived from the Bayesian model combined with these limited sampling strategies were compared with those parameters obtained from the full sample data sets (n = 10) analyzed by weighted nonlinear least squares regression (reference method). The least-bias and most precise sampling times for estimating AUC were 3.5; 3.5 and 9.5; and 0.5, 3.5, and 9.5 h, respectively. At these times, only marginal improvement in precision of the AUC estimate was observed using two versus three samples. However, the precision of the estimate of clearance was not improved using two versus three samples. The sampling times derived from optimal sampling theory were 0.25, 3.5, 8.5, and 24 h and correlated closely to the actual and best empirical sampling times of 0.5, 3.5, 9.5, and 24 h. These results strongly suggest that Bayesian estimation combined with only two optimally timed samples accurately predicts the AUC of CPT-11 and should be useful for implementing adaptive control dosing for monitoring CPT-11 systemic exposure in patients with cancer.

Prognostic factors for response and survival were retrospectively evaluated in 192 previously untreated patients with advanced non-small-cell lung cancer (NSCLC) who had received either vindesine plus cisplatin or mitomycin plus vindesine plus cisplatin as initial treatment. Univariate analysis demonstrated that squamous-cell histology, early stage, and a small number of metastatic sites were favorable prognostic factors for response to chemotherapy. Multivariate analysis using Cox's proportional hazard model indicated that the number of metastatic sites was the only significant pretreatment factor for response (P=0.0005). Multivariate regression analysis revealed that the number of metastatic sites (P=0.0002), sex (P=0.0009), serum albumen levels (P=0.0018), performance status (P=0.0026) and lactic dehydrogenase values (P=0.0026) contributed independently to survival. On the basis of these five prognostic factors, a prognostic index for survival was used to define three prognostic groupings (good, intermediate, and poor) for survival (median survival, 16.5 vs 9.4 vs 4.6 months;P=0.0001). This particular regression model should aid in the design and analysis of new treatment strategies and may be useful for indirect comparisons of different studies carried out in similar patient populations.

We have utilized a human tumor clonogenic assay (HTCA), as a disease-oriented drug screening model of new antitumor drugs, to test the antitumor activity of FR66973 and compared the activity with that of its analogous compound, mitomycin C. The overall in vitro response rate (defined as less than 50% survival of tumor colony forming units) for FR66973 against fresh tumor cells obtained from patients with non-small cell lung carcinoma (NSCLC) was 32%, 50% and 89% at 0.1, 1 and 10 µg/ml, respectively, which was superior to that of mitomycin C at the corresponding concentration. Our data suggest that FR66973 is a promising new drug against NSCLC. If phase I toxicities are not prohibitive, FR66973 may also have good activity against NSCLC in clinical phase II trial.

In vitro antitumor effects of human recombinant tumor necrotizing factor (rH-TNF) were examined against nine lung cancer cell lines including six non small and three small cell lung cancer, four stomach cancer cell lines and 30 freshly isolated lung cancer cell samples by the human tumor clonogenic assay. rH-TNF did not show any inhibitory effect on the colony formations of lung and stomach cancer cell lines, except for PC10 established from squamous cell carcinoma even at the high concentration. The overall response rate of fresh material was 11.5%. The colony formations of only two materials from 20 patients without prior chemotherapy were significantly suppressed by rH-TNF in vitro. Three specimens of adenocarcinoma exhibited more than 70% decrease in colony number by treating with 100 and 1000 u/ml of rH-TNF resulting in the response rate of 15.8% (3/19). From these results, it can be concluded that rH-TNF has modest direct cytotoxic effect on lung cancer, and additional study against adenocarcinoma of the lung might be warranted.

The human tumor colony assay was used to evaluate the effect of a new chemotherapeutic agent (KW2152) on colony inhibition of four non-small cell lung cancer cell lines and a mouse cell line. With continuous exposure experiments, KW2152 induced > 70% colony inhibition of PC-7 (human adenocarcinoma), PC-10 (human squamous cell) and PC-13 (human large cell) at a drug concentration of 10 mcg/ml. In one hour exposure experiments, KW2152 caused a significant reduction in colony formation (< 30% of control) only at the highest concentration tested (100 mcg/ml). KW2152 showed significant in vitro activity against human non-small cell lung cancer cell lines. Due to these promising results, it was suggested that KW2152 should be evaluated in clinical trials.

Abstract Recent advances in pharmacokinetic/pharmacodynamic analysis have been applied to the development of anticancer agents. In addition, there has been an increase in the interest in pharmacokinetic/pharmacodynamic analysis in relation to the field of high-dose (HD) chemotherapy. The basis for investigation of the concept of the dose-response relationship in HD should be the "exposure-response relationship"; this can be investigated in phase I and pharmacology trials of HD chemotherapy designed to define the relationship between escalation of the target drug dose and exposure. Whether pharmacokinetics are linear or nonlinear is important in the determination of optimal dosing. Nonhematological toxicities have become more important than hematological toxicities as pharmacodynamic parameters in HD chemotherapy; however, the relationship between drug exposure and the clinical outcome remains unclear. Cellular concentration and plasma exposure are important predictors of clinical effect. Wide interpatient pharmacokinetic or exposure variability is more important in HD chemotherapy than in conventional-dose chemotherapy due to the increase in the frequency and severity of nonhematological toxicities. Drug-drug interactions are also important issues in HD chemotherapy, although definitive evidence is difficult to obtain. Future investigations of HD chemotherapy are warranted on the basis of pharmacokinetic/pharmacodynamic analysis.

The published reports of phase I clinical trials of anticancer agents conducted in Japan from 1981 to 1991 were reviewed. A total of 56 clinical studies that evaluated 38 different agents were reviewed. An average of five agents were studied each year. A total of 2200 patients had been recruited into the 56 clinical trials conducted during this period. A total of 91 patients (4.1%) responded to the treatment, with 23 showing a complete response (1.1%) and 48, a partial response (2.2%). In all, 62% of the responses were observed when patients were treated with doses ranging from 76% to 125% of the recommended doses for phase II studies. The response rates obtained for hematological malignancies were higher than those reported for other malignancies. The past status of phase I clinical trials in Japan can be summarized as follows. (1) A median of seven institutes participated in a single trial. The number of institutes participating correlated with the number of patients enrolled. However, too many institutes participated in a single phase I clinical trial in some studies. (2) The median duration of study for the clinical trials was 14 months. The duration of study was too long in some studies, considering the small number of patients enrolled. In conclusion, the methodology of phase I clinical trials of anticancer agents conducted in Japan should be improved in an efficient and scientific manner, especially for the testing of imported agents.

The camptothecin derivative 7-ethyl-10-[4-(1-piperidino)-1-piperidino]-carbonyloxy camptothecin (CPT-11) has attracted the attention of clinicians because of its high antitumor activity against refractory solid cancers. We established two CPT-11-resistant cell lines, a non-small-cell lung-cancer cell line (PC-7/CPT-11) from the parental PC-7 line and an ovarian cancer cell line (HAC-2/CPT-11) from the parental HAC-2 line. The mechanisms of resistance to CPT-11 in PC-7/CPT-11 cells were reduced conversion of CPT-11 to its active metabolite SN-38 and point mutation of topoisomerase I. Those in HAC-2/CPT-11 cells were reduction of topoisomerase I activity and decreased sensitivity of topoisomerase to topoisomerase I inhibitors. No point mutation of the topoisomerase was observed in HAC-2/CPT-11 cells. We conducted two phase I trials using CPT-11 in combination with other anticancer agents. One was a phase I trial of CPT-11 and cisplatin given with a fixed dose of vindesine to patients with advanced non-small-cell lung-cancer and the other was a phase I study on a topoisomerase-targeting combination of CPT-11 and etoposide (VP-16) in patients with various malignant solid tumors. The results of the first trial indicated that the recommended dose of CPT-11 for phase II studies was 80 mg/m2 combined with 3 mg/m2 vindesine on days 1 and 8 and 60 mg/m2 cisplatin on day 1. In the second trial, the recommended dose of CPT-11/VP-16 given with recombinant granulocyte colony-stimulating factor (on days 4–17) was found to be 60/60 mg/m2 In both trials, diarrhea and granulocytopenia were considered to be dose-limiting toxicities.

We report the predictive model for the clinical response of new platinum analogs against lung cancer by a bioassay using human lung-cancer cell lines including small-cell (SCLC) and non-small-cell lung cancer (NSCLC). Exponentially growing cells of six different SCLC and sic NSCLC lines were exposed to different concentrations of the three platinum compounds, cisplatin, carboplatin, and 254-S in a double-agar colony-forming cell assay. The concentrations inhibiting 50% of colony formation (IC50 value) for cisplatin, carboplatin and 254-S in SCLC cell lines were significantly lower than those in NSCLC cell lines. A total of 15 patients entered the pharmacological study. In all, 80 mg/m2 cisplatin, 450 mg/m2 carboplatin, and 100 mg/m2 254-S were each given to five patients by intravenous drip infusion. Bioassay as well as chemical assay was achieved by clonogenic techniques using NCI-H-69 (SCLC cell line) and PC-9 (NSCLC cell line) as target cells. Biological comparison of antitumor activity was performed on the basis of the antitumor activity of patients' plasma using the antitumor index (ATI), which was defined as the area under the percentage of colony suppression versus time curve obtained by bioassay and calculated by the trapezoidal rule. When NCI-H-69 and PC-9 were used as target cells for bioassay, colony-inhibitory activity was revealed by the ATIs. The ATIs obtained by bioassay showed better correlation than the AUCs obtained by chemical assay with the clinical response for cisplatin and carboplatin against SCLC and NSCLC, according to the following equation: [Reported Response (%)]=11.5668+0.0014×[ATI] (r=0.97). The response rates for 254-S against SCLC and NSCLC were predicted by this formula to be 40%–65% and 14%–16%, respectively. 254-S is prospectively suspected of having the same, if not more, activity then carboplatin against SCLC and of having almost the same activity as cisplatin against NSCLC.

To analyze the discrepancy between the in vitro response in the clonogenic assay and the clinical response, the time-schedule dependencies of various anticancer drugs were determined by comparing the inhibiting effect against colony formation by PC-7 cells treated with the drugs for 1 h with that of those treated for 24h. According to their schedule dependency the drugs can be divided into a schedule-dependent drug group (5-fluorouracil, methotrexate, bleomycin, pepleomycin, etoposide, cisplatin, teniposide, vindesine, and vinblastine) and a non-schedule-dependent drug group (adriamycin, actinomycin D, ranomustine, mitomycin C, aclacinomycin, daunomycin, nimustine, melphalan, and KW 2083). In the clonogenic assay, the 1-h exposure schedule is appropriate for predicting clinical response for the non-schedule-dependent drugs. However, the effect of the schedule-dependent drugs was underestimated in the same conditions. Therefore, it is necessary to test these drugs in the assay by 24-h exposure for a more accurate assessment of their antitumor activity.

Abstract: Purpose: This study was conducted to determine whether there was any relationship between the adverse toxicity of combination chemotherapy and clinical values including age, sex, creatinine clearance (Ccr), body surface area and relative body weight. Methods: Cisplatin at a dose of 80 mg/m2 on day 1 and etoposide at a dose of 100 mg/m2 on days 1, 2 and 3 were given to 42 consecutive patients with solid tumors. All patients had normal major organ function and received uniform hydration therapy. Results: Body Mass Index as a measure of relative body weight was inversely correlated with the percentage decrease in white blood cells (P = 0.0681) and platelet count (P = 0.0115). Body surface area was also inversely correlated with leukopenia (P = 0.0171) and thrombocytopenia (P = 0.0058). In contrast, age, sex and Ccr had no significant relationship with adverse toxicity. Conclusions: It is concluded that dose adjustment of combination chemotherapy with cisplatin and etoposide according to age or ideal body weight is not appropriate and that a conventional dose modification method based solely on body surface area is probably not sufficient to reduce interpatient variability of cancer chemotherapy. A pharmacokinetic and pharmacodynamic study of combination chemotherapy is warranted to establish the ideal dose modification method.

A total of 68 patients with non-small-cell lung cancer who either had not previously been treated (38) or had undergone prior therapy (30) were treated in a phase II study of (glycolate-O,O′) diammineplatinum(II) (NSC 375 101D; 254-S), a new platinum complex. The drug was given as a single intravenous infusion at a dose of 100 mg/m2every 4 weeks. All 68 patients could be evaluated for response and 62, for toxicity. Objective responses were seen in 10 of 68 cases (14.7%; 95% confidence interval, 7.3%–25.4%), and the median duration of response was 15 weeks (range, 8–23 weeks). The response rates were similar for previously untreated and treated patients (13% and 17%, respectively), including three previously treated with cisplatin. Myelosuppression was the dose-limiting toxicity. Thrombocytopenia (<100,000 platelets/mm3) and leukocytopenia (<3,000 WBC/mm3) were observed in 22 (35%) and 18 (29%) patients, respectively. Mild to moderate nausea and vomiting occurred in 45 cases (73%). No significant renal or neurotoxicity was observed. We conclude that as a single agent, 254-S is well tolerated but appears to have marginal activity against non-small-cell lung cancer.

A Phase II study of paclitaxel in patients with primary advanced or metastatic breast cancer was conducted by a cooperative study group consisting of 16 institutions in Japan. Paclitaxel at a dose of 210 mg/m2 was intravenously infused over 3 hours, along with premedication to prevent hypersensitivity reactions. The course was repeated at 21-day intervals. Of 62 eligible patients, 60 were evaluable for toxicity and 59 were evaluable for efficacy. Forty-five patients were previously treated with anthracyclines. Twenty-one of 59 patients (35.6%) had a major objective response including 2 CRs and 19 PRs (95% confidence interval, 23.6–49.1%). A response rate of 35.5% (CR1, PR10) was observed in 31 patients refractory to the anthracyclines containing prior metastatic chemotherapy. Median (range) time was 41 (6–100) days to onset of and median duration of response was 125 (36–305) days. Toxicities included leukopenia (grade 3, 4: 67%), anemia (grade 1–3: 80%), thrombocytopenia (grade 1: 8%), alopecia (grade 3: 43%), peripheral neuropathy (grade 1–3: 93%), arthralgia (59%), myalgia (46%), nausea and vomiting (40%), fever (33%), allergic reaction (grade 3: 2%) and hypotension (grade 3: 5%). All toxicities were tolerable and manageable. Paclitaxel intravenously infused over 3 hours demonstrated a significant antitumor activity for metastatic breast cancer. Furthermore, paclitaxel exhibited non-cross resistance to anthracycline. Paclitaxel administered as a convenient 3-hour infusion is effective for patients with metastatic breast cancer and has an acceptable toxicity profile.

A total of 190 patients with unresectable non-small cell lung cancer (NSCLC) were analyzed retrospectively using eight pretreatment and three treatment-related prognostic factors in terms of influence on survival. All the patients received chemotherapy with or without chest irradiation, according to the protocol of phase II or phase III trials of the National Cancer Center Hospital Tokyo between April 1980 and December 1985. The eight pretreatment factors selected were performance status, sex, stage, age, histology, and metastasis to brain, bone or, liver. Three treatment-related factors were radiation therapy to the primary site, response to chemotherapy, and treatment period, before or after clinical adminsitration of cis-diamminedichloroplatinum (II) (CDDP). Of the 190 patients, 71 (37.4%) were alive for more than 1 year, but only 17 patients (8.9%) survived 2 years after the initiation of chemotherapy. By univariate analysis, performance status 0–1, female, no metastasis to bone or liver, response to chemotherapy, and treatment period after CDDP were considered to be favorable prognostic factors. By multiregression analysis, performance status, sex, and treatment period after CDDP proved to be important factors for long-term survival. Consideration of these prognostic factors could enable the results of chemotherapy to be more accurately evaluated, and stratification of patients with advanced NSCLC based on performance status and sex before entry into a randomized controlled trial is recommended.

The cytotoxicity of spleen lymphocytes against YAC-1 cells, against syngeneic B-16 and F-10 melanoma cells was augmented not only by incubation of spleen lymphocytes with human recombinant interleukin-2 (rIL-2) in vitro, but also by injectingC57BL/6 mice with high dose rIL-2 for more than 3 consecutive days. In animals injected s.c. with multiple high dose rIL-2, the numbers of tumor nodules in the lung were significantly decreased 21 days after i.v. tumor inoculation. In addition, in these groups of animals no liver metastases were observed although live metastases were detected in 6/11 control mice.

Carboplatin, a second generation cisplatin analogue, was tested for induction of sister chromatid exchange (SCE) as well as chromosomal aberrations in human lymphocytes in vitro and in vivo. A dose-dependent effect was observed for increased frequency of metaphases with SCE (r=0.984, P(0.001) as well as chromosomal aberrations (r=0.994, P(0.001), primarily chromatid gap or break, in vitro. SCE induction by carboplatin was less than that by cisplatin at the same concentration. When patients were treated with a single dose of carboplatin at a dose of 450 mg/m2, the frequency of SCE and chromatid type aberrations increased significantly. However, even when considering dose and peak plasma concentration in patients receiving carboplatin, it appears that the ability of carboplatin to induce SCE and chromosomal aberrations is weaker than that of cisplatin. SCE frequencies induced by carboplatin decreased with time going by, and in one patient who was tested 5 weeks after treatment, SCE frequency showed a decrease to the pretreatment level. It thus appears that carboplatin has an improved therapeutic index over the parent compound, cisplatin, because of its less mutagenic or carcinogenic hazard, in addition to the largely reduced incidence of untoward effects.

The effects of carboplatin and cisplatin on colony formation in stomach and lung cancer cell lines were examined and compared. The colony-inhibitory activity of carboplatin against stomach and lung cancer cell lines was similar to that of cisplatin when one-tenth of the peak plasma concentration of each drug was used (r=0.80). One of the four stomach cancer cell lines was sensitive to carboplatin although all the stomach cancer cell lines were resistant to cisplatin. Of the three small cell lung cancer cell lines tested, two were sensitive to both carboplatin and cisplatin; and only one cell line (N857) was resistant to cisplatin; all the non-small cell cancer cell lines tested were resistant to both drugs. On the basis of these preliminary results, we suggest that carboplatin has potential therapeutic activity against stomach cancer and should be evaluated carefully from this aspect.

The pharmacokinetics of (glycolato-0,0')-diammine platinum (II) (254-S; NSC 375101D), one of the new platinum analogues, was examined in a phase I study of this drug and compared with that of cisplatin and carboplatin. All drugs were given in short-term (30-min) i.v. drip infusions; the doses of 254-S, cisplatin, and carboplatin were 100, 80, and 450 mg/m2, respectively. Platinum concentrations in whole plasma, plasma ultrafiltrate, and urine were determined by atomic absorption spectrometry. After the infusion, the plasma concentration of total platinum for the three agents decayed biphasically. Ultrafilterable platinum in plasma decreased in a biexponential mode after infusions of 254-S and carboplatin, whereas the free platinum of cisplatin showed a monoexponential disappearance. The peak plasma concentrations and AUC for free platinum were 5.31 µg/ml and 959 µg/min per ml for 254-S, 3.09 µg/ml and 208 µg/min per ml for cisplatin, and 19.90 µg/ml and 3446 µg/min per ml for carboplatin, respectively. The mean ratio of plasma ultrafilterable platinum to total platinum were calculated, and the results showed that the protein-binding abilities of 254-S and carboplatin were almost identical. More than 50% of the 254-S was excreted in the urine within the first 480 min after its administration. Thrombocytopenia was reported as a dose-limiting toxicity for both 254-S and carboplatin. This similarity in side effects may mainly be due to the comparable pharmacokinetic behavior of these two platinum compounds.