Selectivity of compounds isolated from the leaves of Nerium indicum Mill. on various human cancer cell lines.

The leaves of Nerium indicum Mill. have been utilized traditionally to cure cancer. By Bioassay (BST) guided isolation method, six compounds were isolated from the CHCl3 extract of the leaves. Selectivity of these compounds (in 0.6-12,500 ng/ml) was tested on various human cancer (MCF7, EVSA-T, T47D, H226, IGROV, A498, WIDR, M19, HeLa) and normal (Vero) cells in vitro. Doxorubicin and cysplatin were used as positive controls. The result indicated that NiO2D (5alpha-oleandrin) possessed the best cytotoxic effect on HeLa cells (IC50, 8.38 x10(-6) mM) and NiO2C (16, 17-dehidrodeasetil-5alpha-oleandrin) on A498 cells (IC50, 1.43 x 10(-6) mM). Those two compounds were not cytotoxic to normal cell.

A pharmacokinetic interaction study of docetaxel and cisplatin plus or minus 5-fluorouracil in the treatment of patients with recurrent or metastatic solid tumors.

BACKGROUND: The purpose of this study was to look at the pharmacokinetics of docetaxel, cisplatin-derived platinum and 5-fluorouracil (5-FU), when used in combination, to exclude potential clinically relevant pharmacokinetic interactions. METHODS: Fifteen patients with recurrent or metastatic solid tumors were randomized to receive docetaxel 75 mg/m2 and cisplatin 75 mg/m2 in the first treatment course on day 1 and the same combination plus 5-FU 750 mg/m2/day on days 1-5 in the second course, or the two treatment courses in reversed order. Cycles were repeated every 3 weeks. A pharmacokinetic analysis was performed during the first two cycles. RESULTS: Full pharmacokinetic data was available for 12 of the 15 patients. Treatment was tolerated well, with frequency of toxicity consistent with the safety profile known for docetaxel, cisplatin and 5-FU. Mean clearance values for docetaxel and cisplatin showed no statistically significant difference across the "triple" and the "double" combination treatments, and the mean pharmacokinetic parameters of all agents were within the ranges for previously reported single agent treatment. CONCLUSION: No clinically relevant pharmacokinetic interactions between docetaxel, cisplatin and 5-FU used in combination were noticed in this study.

In vitro studies on the enhancement of Rauscher virus-induced erythroblastosis by complete Freund's adjuvant in BALB/c mice.

Inoculation of complete Freund's adjuvant (CFA) into BALB/c mice either before or after infection with Rauscher murine leukemia virus (MuLV-R) led to an acceleration of the disease as determined by spleen weight. Treatment with CFA also induced a higher number of spleen erythroblast foci and, in the bone marrow, erythropoietin-independent cells that produced erythroid colonies in vitro. CFA induced in the bone marrow not only an increase in myeloid progenitor cells that can produce colonies in agar, but an ever larger increase in the number of erythroid colony-forming cells. Virus-induced erythroblastosis was probably enhanced by CFA due to the production of many target cells. The more primitive burst-forming cell, which produced large colonies of erythroid cells after 10 days in culture, was also physiologically transformed in MuLV-R-infected mice; bursts could be formed by cells of such animals in the absence of erythropoietin.

Hormone-independent in vitro erythroid colony formation by bone marrow cells from Rauscher virus-infected mice.

Bone marrow cells from BALB/c mice infected with Rauscher erythroblastosis virus produced five to twenty-five times more erythroid colonies in vitro in the absence of erythropoietin (EP) as compared to normal cells. A good correlation existed between the state of the disease and the number of hormone-independent erythroid colony-forming cells (CFU-E). A significant number of hormone-independent CFU-E was found as early as 3 days after infection. A linear relationship existed between the number of cells plated and the number of erythroid colonies formed in vitro. Addition of EP did not enhance colony formation, even at low cell concentrations. Feeder layer experiments demonstrated that EP-independent colony formation was not due to the production of endogenous EP. Repeated injections of phenylhydrazine into normal mice did not lead to the loss of EP responsiveness in vitro; this indicated that the hormone independency induced by the virus was not due to continuous erythropoietic stimulation in vivo. Besides hormone independency, the CFU-E from infected mice required less serum in the culture medium. Normal erythroid colonies regressed after 4 days of culture, but EP-independent colonies from infected mice persisted for more than 2 weeks. These three phenomena may be regarded as indicative for a physiologic transformation.

Rescue of a transforming virus from a spontaneous nonproducing osteosarcoma in BALB/c mice.

Cells from spontaneous osteosarcoma V793 that originated in a 19-month-old female BALB/c mouse were cultured. They did not produce a C-type oncovirus as determined by extracellular reverse transcriptase assay and cytoplasmic immunofluorescence. After cocultivation with Balb/3T3 cells chronically infected with a murine leukemia virus (MuLV), a focus-forming principle that transformed 3T3 cells, secondary BALB/c mouse embryo and WAG/Rij rat embryo fibroblasts were rescued. The transformation could be inhibited by antiserum to MuLV.

Expression of mdr1 and mdr3 multidrug-resistance genes in human acute and chronic leukemias and association with stimulation of drug accumulation by cyclosporine.

We determined the expression levels of the mdr1 and mdr3 multidrug-resistance genes (also known as PGY1 and PGY3, respectively) in peripheral blood cells from 69 adult patients with acute and chronic leukemias, using an RNase protection assay. Expression of mdr1 was found in samples from patients with acute nonlymphocytic leukemia (13 of 17), chronic myelocytic leukemia (CML, chronic phase, 10 of 10; blast crisis, three of four), acute lymphocytic leukemia (ALL, eight of 11), B-cell chronic lymphocytic leukemia (B-CLL, 17 of 17), hairy cell leukemia (HCL, one of two), and T-cell prolymphocytic leukemia (one of one), but not in B-cell prolymphocytic leukemia (B-PLL, 0 of seven). Expression of mdr3 was only detected in samples from B-cell lymphocytic leukemias: CML, lymphoid blast crisis (one of one), B-cell ALL (two of two), B-CLL (17 of 17), B-PLL (seven of seven), and HCL (two of two). In vitro drug uptake studies by on-line flow cytometry showed that in leukemia cells expressing either mdr1 or mdr3, the steady-state accumulation of daunorubicin could be significantly increased by addition of cyclosporine and, to a lesser extent, by verapamil. Because cyclosporine and verapamil are known as inhibitors of the mdr1-encoded P-glycoprotein drug-efflux pump, and because the mdr1 and mdr3 genes are highly homologous, our data suggest that the mdr3 gene encodes a functional drug pump in B-cell lymphocytic leukemias. The results of this study may have implications for clinical therapy for acute or chronic leukemias expressing the mdr1 or mdr3 gene, in particular, treatment with combinations of cytotoxic drugs plus agents that reverse multidrug resistance. Since mdr1 and mdr3 are frequently expressed in untreated as well as treated leukemia, such combination therapy should be considered for untreated patients as well as treated patients.

Cell density-dependent growth in agar of bone marrow cells from tumor-bearing BALB/c mice in the absence of a colony-stimulating factor.

Bone marrow cells from BALB/c mice with myeloid leukemia, lymphosarcoma, erythroblastosis, or mammary tumor produce small clusters in semisolid agar cultures in the absence of specific colony-stimulating factor. This spontaneous growth is observed only when high cell numbers (5 x 10 5 cells/ml) are plated. The phenomenon was encountered only when mice had an elevated number of mature or immature granulocytes in the peripheral blood. Removal of the adherent cells from the bone marrow did not abolish spontaneous growth, indicating that this colony-stimulating factor independency is not due to a high number of colony-stimulating cells in the bone marrow cells. This excluded the possibility that the spontaneous growth was due to a high endogenous stimulating activity of the bone marrow from tumor-bearing mice.

In vitro growth characteristics of virally transformed murine myeloid cells.

Bone marrow from normal BALB/c mice, mice with myeloid leukemia induced by Soule myeloid leukemia virus, and mice with virally induced mammary carcinoma was cultured in semisolid agar. Bone marrow from either leukemic or mammary tumor-bearing mice produces more clones in vitro in the presence of a specific colony-stimulating factor. However, in all cases, the myeloid progenitor cells have similar requirements for the colony-stimulating factor. The optimum condition for growth in all instances is 7% fetal calf serum + 7% horse serum + 7% tryptose phosphate broth. Decrease in the concentration of these three constituents has a less drastic effect on in vitro proliferation of bone marrow cells from leukemic mice. Some cells from Soule virus-induced leukemias even grew in the absence of serum. The combination of suboptimal amounts of serum and colony-stimulating factor is used as a tool for detecting cells with altered growth characteristics in bone marrow of leukemic mice. During the progression of the leukemia, there is an increase in the amount of transformed colony-forming cells per 5 X 10(4) bone marrow cells. The increase is already noticeable 4 weeks after inoculation, when no clinical signs of the leukemia are present, and reaches a maximum of about 20%.

Differences in the pharmacokinetics of daunomycin in normal and leukemic rats.

We compared the pharmacokinetics of daunomycin (7.5 mg/kg i.v. bolus injection) in normal and leukemic rats using a leukemia model which resembles acute myeloid leukemia in humans. Due to a more rapid decrease in plasma concentration, the area under the plasma concentration/time curve (AUC) for up to 2 h after drug injection was smaller (2.2 times) in the leukemic rats than that for normals. However, due to higher plasma levels during the drug elimination phase, the total AUC0----infinity was somewhat larger (1.3 times) in the leukemic rats. In the leukemia-infiltrated organs (spleen, liver, and lungs), significantly higher daunomycin concentrations (per gram wet weight) were found than in those obtained from normal rats. In contrast, femoral bone marrow from leukemic rats contained less daunomycin (per 10(9) nucleated cells) than did normal marrow. Quantification of the daunomycin uptake in vitro by flow cytometry showed that leukemic cells from bone marrow and spleen have an equal net drug uptake. Our data suggest that, in the presence of a high leukemic cell load, the intravenously injected daunomycin is rapidly taken up and retained by the leukemic tumor mass in, e.g., spleen, liver, and lungs, and that, as a consequence of this, the femoral marrow functions as a kind of pharmacological sanctuary.

Quantitative flow cytometric determination of anthracycline content of rat bone marrow cells.

Flow cytometry was used to determine the daunomycin content of rat bone marrow cells after incubation in vitro. The spontaneous fluorescence of daunomycin was measured upon excitation with laser light at 488 nm. Forward and perpendicular light scatters of the cells were simultaneously measured to allow identification of granulocytic and lymphocytic subpopulations. A linear relationship was found for a 30-min exposure between the drug concentration (ranging from 0.2 to 3 micrograms/ml) in the incubation medium and the fluorescence intensity for both lymphocytes and granulocytes. Dead cells contaminating cell suspensions showed several times higher daunomycin fluorescence than did viable cells. In fixed cells, the fluorescence reflects daunomycin bound to DNA, since the fluorescence intensity of daunomycin-treated fixed cells returns to the level of unstained cells after DNase treatment. Quantitation of the cellular drug concentration was done by exposing cells in vitro to varying doses of [3H]daunomycin. At each drug concentration, the fluorescence intensity of the cells was measured using flow cytometry. Granulocytes and lymphocytes were sorted on the basis of light scatter. The amount of intracellular drug was determined for both cell populations at each drug dose by measuring the radioactivity in 600,000 sorted cells. The concentration per cell was on the order of 10(-18) mol. For both the granulocytic and the lymphocytic subpopulations, a linear relationship was found between drug-related radioactivity and fluorescence intensity.

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications.

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios.

SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line.

The therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin. Heterologous expression of the human SKY1 homologue SRPK1 (serine/arginine-rich protein-specific kinase) in SKY1 deletion mutant yeast cells restored cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity gene, the inactivation of which could lead to cisplatin resistance. Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity and resistance in human ovarian carcinoma A2780 cells using antisense oligodeoxynucleotides. Treatment of A2780 cells with antisense oligodeoxynucleotides directed against the translation initiation site of SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold resistance to cisplatin. The human SRPK1 gene has not been associated with drug resistance before. Our new findings strongly suggest that SRPK1 is involved in cisplatin-induced cell kill and indicate that SRPK1 might potentially be of importance for studying clinical drug resistance.

Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure.

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m(2) (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non-protein-bound cisplatin in plasma by atomic absorption spectrometry. RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL(free)) was 57.1 +/- 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m(2) (mean, 1.86 +/- 0.19 m(2)), with an interpatient variability of 10.4%. When CL(free) was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL(free) and BSA (r = 0.42). Intrapatient variability in CL(free), calculated from 90 patients was 12.1% +/- 7.8% (range, 0.30% to 32.7%). CONCLUSION: In view of the high interpatient variability in CL(free) relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

Multidrug resistant cells with high proliferative capacity determine response to therapy in acute myeloid leukemia.

High spontaneous proliferation of acute myeloid leukemia (AML) in vitro is an unfavorable, tumor-specific prognostic factor. We investigated the frequency of drug-resistant tumor cells with high proliferating capacity in de novo AML and analyzed the expression of multiple resistance parameters in relation to the response to chemotherapy and overall survival. Thirty-eight patients were included in this study. P-glycoprotein (P-gp) expression was found in 28/38 patients and was associated with lower intracellular accumulation of DNR (P = 0.0001). Thirty-five out of 38 patients were treated with 1-2 regimens of daunorubicin (DNR)/cytarabine (Ara-C), and 57% attained a complete remission (CR). Failure to achieve a CR correlated with autonomous growth (P = 0.0064), CD34 and P-gp expression alone (P = 0.0005 and P = 0.048 respectively), and with simultaneous expression of P-gp and CD34 (P = 0.0001), but not with expression of the non-P-gp drug resistance associated-protein (p110), the multidrug resistance-associated protein (MRP), Ara-CTP formation or Ara-C incorporation, respectively. AML cells with CD34/P-gp double expression were more frequently observed in samples with high autonomous growth (P = 0.003). The median survival was 6 months in CD34+/P-gp+ patients as compared with 15 months in other AML patients (P = 0.003). In patients with de novo AML who fail on chemotherapy, a population of autonomously proliferating, immature AML cells with a multidrug resistant phenotype can be recognized. These cells thus show primary resistance to chemotherapy and have the potential for rapid regrowth, leading to resistant disease.

Expression of the multidrug resistance-associated protein (MRP) in acute and chronic leukemias.

We determined the expression of the multidrug resistance-associated protein (MRP), a new putative transmembrane drug transporter, in peripheral blood cells from healthy volunteers as well as from 60 patients with acute or chronic leukemia, using an RNase protection assay. MRP appeared to be ubiquitously expressed at low levels in all nonmalignant hemopoietic cell types, reflecting its basal constitutive expression. In acute myelocytic leukemia (AML) (n = 16), one of nine untreated patients and two of seven patients with prior chemotherapy showed significant hyperexpression of MRP. In chronic lymphocytic leukemia (CLL) (n = 21), either treated (n = 8) or untreated (n = 13), a high percentage (15 of 21: 71% had relatively high expression levels of the MRP gene. In contrast, low MRP expression levels were detected in acute lymphocytic leukemia (n = 14), and in chronic myelocytic leukemia (n = 9). DNA analysis by Southern blotting did not reveal amplification of the MRP gene in the leukemia samples, including those with elevated MRP mRNA levels. We conclude that relatively high expression of MRP is occasionally observed in AML and at high frequency in CLL, irrespective of treatment, probably due to transcriptional activation and/or increased mRNA stability.

High expression of the multidrug resistance P-glycoprotein in high-risk myelodysplasia is associated with immature phenotype.

The expression of the multidrug resistance (MDR-1) gene product, P-170 glycoprotein (P-170) was investigated in 26 patients with low-risk (n = 9) or high-risk (n = 17) myelodysplastic syndrome (MDS), using a panel of monoclonal antibodies to P-170 (C219, JSB1, C494, MRK16) and quantitative analysis of MDR-1 mRNA. P-170 membrane staining was demonstrated in bone marrow blast cells of 14/17 HR-MDS and in 2/9 LR-MDS patients (p < 0.01). P-170 expression was associated with the presence of blast cells characterized by an immature or early myeloid phenotype as defined by CD34 expression (p = 0.034), CD13 or CD33 expression (p = 0.0006), or CD13/33 plus terminal deoxynucleotidyl transferase (TdT) double expression (p = 0.04). With double fluorescence analysis, P-170 expression was observed in a subset of CD34+ cells, but not in CD34- cells. P-170 expression was present in 13/15 (86%) patient samples with an abnormal karyotype as compared with 3/10 samples (30%) with a normal karyotype (p < 0.05). Nine of these 15 patients had a loss or a deletion of chromosome 7. Thirteen out of 16 (81%) MDR-1 positive patients developed acute leukemia versus two of ten (20%) MDR-1 negative patients (p = 0.025). It is concluded that MDR-1 expression in MDS is present in cells with an immature phenotype and is frequently observed in patients who have an abnormal karyotype and a high risk of leukemic transformation.

Role of intestinal P-glycoprotein in the plasma and fecal disposition of docetaxel in humans.

Multidrug resistance (MDR)-1-P-glycoprotein (P-gp) is a drug-transporting protein that is abundantly present in biliary ductal cells and epithelial cells lining the gastrointestinal tract. Here, we have determined the role of P-gp in the metabolic disposition of the antineoplastic agent docetaxel (Taxotere) in humans. Pharmacokinetic profiles were evaluated in five cancer patients receiving treatment cycles with docetaxel alone (100 mg/m2 i.v. over a 1-h period) and in combination with a new potent inhibitor of P-gp activity, R101933 (200-300 mg b.i.d.). The terminal disposition half-life and total plasma clearance of docetaxel were not altered by treatment with oral R101933 (P > or = 0.27). The cumulative fecal excretion of docetaxel, however, was markedly reduced from 8.47 +/- 2.14% (mean +/- SD) of the dose with the single agent to less than 0.5% in the presence of R101933 (P = 0.0016). Levels of the major cytochrome P450 3A4-mediated metabolites of docetaxel in feces were significantly increased after combination treatment with R101933 (P = 0.010), indicating very prominent and efficient detoxification of reabsorbed docetaxel into hydroxylated compounds before reaching the systemic circulation. It is concluded that intestinal P-gp plays a principal role in the fecal elimination of docetaxel by modulating reabsorption of the drug after hepatobiliary secretion. In addition, the results indicate that inhibition of P-gp activity in normal tissues by effective modulators, and the physiological and pharmacological consequences of this treatment, cannot be predicted based on plasma drug monitoring alone.

Expression of the multidrug resistance-associated protein (MRP) gene in human cancers.

We determined the expression of a newly recognized drug resistance gene, the multidrug resistance-associated protein (MRP) gene, [Cole et al., Science (Washington DC), 258: 1650-1654, 1992], in normal human tissues and in >370 human tumor biopsies using a quantitative RNase protection assay and immunohistochemistry. MRP mRNA appeared to be ubiquitously expressed at low levels in all normal tissues, including peripheral blood, the endocrine glands (adrenal and thyroid), striated muscle, the lymphoreticular system (spleen and tonsil), the digestive tract (salivary gland, esophagus, liver, gall bladder, pancreas, and colon), the respiratory tract (lung), and the urogenital tract (kidney, bladder, testis, and ovary). The human cancers analyzed could be divided into three groups with regard to MRP expression. Group 1 consists of tumors that often exhibit high to very high MRP mRNA levels (e.g., chronic lymphocytic leukemia). Group 2 comprises the tumors that often exhibit low, but occasionally exhibit high MRP mRNA expression (e.g., esophagus squamous cell carcinoma, non-small cell lung cancer, and acute myelocytic leukemia). Group 3 comprises the tumors with predominantly low levels of MRP mRNA, comparable to the levels found in normal tissues (e.g., other hematological malignancies, soft tissue sarcomas, melanoma, and cancers of the prostate, breast, kidney, bladder, testis, ovary, and colon). Using the MRP-specific mAbs MRPr1 and MRPm6, we confirmed the elevated MRP mRNA levels in tumor tissues by immunohistochemistry. We conclude that hyperexpression of MRP is observed in several human cancers, and that additional studies are needed to assess the clinical relevance of MRP.

Pharmacokinetics and bioavailability of oral 9-aminocamptothecin capsules in adult patients with solid tumors.

Preclinical studies indicate enhanced antitumor activity of 9-amino-20(S)-camptothecin (9-AC) when it is administered in a manner that provides prolonged systemic exposure. In view of this observation, the pharmacokinetics and oral bioavailability of 9-AC polyethylene glycol 1000 capsules were evaluated in 12 patients with solid tumors. Patients were randomized to receive either 1.5 mg/m2 9-AC p.o. on day 1 and 1.0 mg/m2 9-AC i.v. on day 8 or vice versa. Serial plasma samples were collected up to 55 h after dosing and analyzed for 9-AC by liquid chromatography. Plasma concentrations of the lactone and carboxylate forms of 9-AC rapidly reached an equilibrium, with the active lactone accounting for < 10% of total drug at the terminal disposition phase. The drug demonstrated peak levels at 1.2 h and an overall bioavailability of 48.6+/-17.6% (range, 24.5-80.4%), indicating significant systemic exposure to the drug, which may enable chronic oral treatment.

Clinical pharmacokinetics and metabolism of irinotecan (CPT-11).

CPT-11 belongs to the class of topoisomerase I inhibitors, and it acts as a prodrug of SN-38, which is approximately 100-1000-fold more cytotoxic than the parent drug. CPT-11 has shown a broad spectrum of antitumor activity in preclinical models as well as clinically, with responses observed in various disease types including colorectal, lung, cervical, and ovarian cancer. The pharmacokinetics and metabolism of CPT-11 are extremely complex and have been the subject of intensive investigation in recent years. Both CPT-11 and SN-38 are known in an active lactone form and an inactive carboxylate form, between which an equilibrium exists that depends on the pH and the presence of binding proteins. CPT-11 is subject to extensive metabolic conversion by various enzyme systems, including esterases to form SN-38, UGT1A1 mediating glucuronidation of SN-38, as well as CYP3A4, which forms several pharmacologically inactive oxidation products. Elimination routes of CPT-11 also depend on the presence of drug-transporting proteins, notably P-glycoprotein and canalicular multispecific organic anion transporter, present on the bile canalicular membrane. The various processes mediating drug elimination, either through metabolic breakdown or excretion, likely impact substantially on interindividual variability in drug handling. Strategies to individualize CPT-11 administration schedules based on patient differences in enzyme or protein expression or by coadministration of specific agents modulating side effects are under way and may ultimately lead to more selective chemotherapeutic use of this agent.