| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
PHARMACOKINETICS AND PHARMACODYNAMICS |
From Dr. Reddy's Laboratories Ltd., Hyderabad, India (A. Chatterjee, R. N. V. S. Mamidi, K. Katneni, V. V. Upreti, S. Subramaniam, N. R. Srinivas) and Nizam's Institute of Medical Sciences, Hyderabad, India (R. Digumarti, A. Surath, M. L. Srinivas, S. Uppalapati, S. Jiwatani). Source of research support: Dr. Reddy's Laboratories Ltd., Hyderabad, India.
Address for reprints: Dr. Nuggehally R. Srinivas, FCP, Dr. Reddy's Laboratories, Discovery Research, Bollaram Road, Miyapur, Hyderabad—500 049, India.
 |
ABSTRACT |
|---|
 TOP ABSTRACT METHODSRESULTSDiscussionACKNOWLEDGEMENTSREFERENCES |
|---|
Key Words: DRF-1042 • camptothecin • pharmacokinetics • pharmacodynamics • maximum tolerated dose • dose-limiting toxicities • cancer
Treatment of mammalian cells with CPT results in fragmentation of DNA,14,15 inhibition of DNA synthesis,16 and impairment of cell division. Mammalian topo-I is a target of CPT.17,18 Topo-I is a nuclear enzyme that has an important role in DNA replication.19,20 It forms a covalent bond at the 3'-DNA terminus, known as the topo-I/DNA cleavable complex.21-24 This relaxes supercoiled DNA, causing single-strand breaks that allow the intact strands to pass. After completion of strand passage, topoisomerases religate the DNA. CPTs bind to the topo-I/DNA complexes, resulting in single-strand breaks that cannot be religated.17-28 Of particular interest is the lack of cross-resistance of CPTs to other drugs affected by the multidrug-resistant phenotype.29
DRF-1042 (5(RS)-(2-hydroxyethoxy)-20(S)-CPT) (Figure 1), a semisynthetic derivative of CPT, is the first anticancer agent to enter clinical development in India. Like other CPT analogs, it undergoes a reversible, pH-dependent hydrolysis from an active lactone species to an inactive carboxylate form. The compound was sparingly soluble in water and highly protein bound. DRF-1042 was highly active in vitro against a broad spectrum of human tumor cell lines, with an average GI50 value in the order of 10-6 M, and showed lack of breast cancer resistance protein (BCRP) substrate activity. Marked in vivo activity was observed upon oral as well as intravenous administration at 28 to 35 mg/kg in athymic mice against a variety of subcutaneous xenografts derived from adult tumors, including colon, lung, prostate, and kidney tumors, and in xenografts derived from pediatric tumors such as rhabdomyosarcoma.
|
This report summarizes the results of a phase I trial and pharmacokinetic study of DRF-1042 given orally for 5 days for 2 consecutive weeks, repeated every 3 weeks in adult patients with refractory cancer.
|
METHODS |
|---|
|
TOPABSTRACTMETHODSRESULTSDiscussionACKNOWLEDGEMENTSREFERENCES |
|---|
Patients
Between October 2000 and February 2002, patients admitted to the Nizam's Institute of Medical Sciences (NIMS), Hyderabad, India, and meeting the following criteria were entered in this phase I trial: (1) histologically or cytologically confirmed diagnosis of a malignant solid tumor refractory to conventional treatment or for which no established therapy exists; (2) ages 18 to 75 years; (3) Eastern Cooperative Oncology Group (ECOG) PS 
2; (4) measurable or assessable disease; (5) estimated life expectancy 
12 weeks; (6) adequate bone marrow function: WBC count 4 x 109/L, platelet count 100 x 109/L, and hemoglobin 10 g/dL; (7) adequate liver function: bilirubin within normal limits and alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline phosphatase 2 times normal (unless due to bone metastases); (8) adequate renal function: creatinine 1.5 times normal; and (9) recovery from toxicity of previous treatments. Patients were ineligible if they had (1) active infection, (2) pregnancy or lactation, (3) central nervous system tumors, (4) major surgery within 2 weeks or radiotherapy or chemotherapy within 4 weeks before entry (6 weeks for mitomycin or nitrosoureas), and (5) radiotherapy to > 10% of bone marrow. The NIMS investigational review board approved the study protocol. Informed consent was obtained from each subject.
DRF-1042 Formulation
DRF-1042 was manufactured at Dr. Reddy's Laboratories (Hyderabad, India) as an oral suspension with dimethylsulfoxide, Span-80, Cremophor, ethyl alcohol, sodium taurocholate, citric acid, and glycerol as its excipients, prepared in eight dose strengths—namely, 2 mg/5 mL, 5 mg/5 mL, 10 mg/5 mL, 20 mg/5 mL, 40 mg/5 mL, 60 mg/5 mL, 75 mg/5 mL, and 90 mg/5 mL. Quality controls were in place to ensure that accurate dosages were produced for this phase I study. The dosage strengths were evaluated and verified by a high-pressure liquid chromatography (HPLC) assay. The stability of DRF-1042 in such a suspension at room temperature (25°C) was up to 1 year.
Dosage and Administration
All patients were hospitalized for the duration of the treatment. DRF-1042 was administered orally for 5 consecutive days for 2 weeks every 3 weeks. This 3-week period constituted one cycle or course of treatment. Patients were fasted overnight prior to a morning drug administration. Patients were discharged at the start of the 3rd week of each cycle.
The starting dose of DRF-1042, 1.5 mg/m2/day, was 10% of the murine MTD (LD10). Based on an accelerated design,30 1 patient was treated at the first dose level. One new patient was treated in subsequent cohorts with 100% dose escalation until the mouse MTD was crossed. At this time, 3 new patients were accrued at each dose level. Subsequent cohorts of 3 patients were treated with 50% dose escalation. If DLT was noted in 2 of 3 patients at any dose level during the first course of therapy, 3 additional patients were enrolled at the same level. If DLT was noted in more than 2 of 6 patients at any dose level during the first course of therapy, the MTD was exceeded, and 3 more patients were treated at the next lower dose level.
Cycles could be repeated in the absence of irreversible DLT. Doses could also be escalated if no grade 2 or higher toxicity was observed during the previous cycle. For any grade 4 hematologic or grade 3 or higher gastrointestinal (except emesis) toxicity, drug administration was withheld until complete recovery. Patients could continue treatment if they did not develop progressive disease (PD) or unacceptable toxicity. Patients with reversible DLT could continue treatment at the next lower dose level. Once a dose was reduced, the patient received that reduced dose for the entire remaining treatment course. Patients were taken off protocol in case of PD.
Pretreatment and Follow-up Studies
History and physical examination, including performance status, routine laboratory measurements, chest x-rays, and resting 12-lead electrocardiograms, were obtained at baseline and before each subsequent course. Routine laboratory studies included a complete blood count (CBC), including WBC differential; sodium, potassium, chloride, calcium, phosphorus, magnesium, bilirubin, total protein, serum albumin, ALT, AST, alkaline phosphatase, lactate dehydrogenase, amylase, blood urea nitrogen, serum creatinine, uric acid, cholesterol, and glucose levels; prothrombin time; partial thromboplastin time; and urinalysis. During the study, CBC and serum chemistries were measured two to three times a week. Patients with measurable disease had appropriate diagnostic imaging studies at baseline and every two cycles thereafter to assess tumor response.
Toxicity and Response Evaluation
Toxicities were graded according to NCI common toxicity criteria (version 2). Patients with measurable disease at enrollment were considered evaluable for response. Response was assessed according to World Health Organization (WHO) criteria31 if a minimum of 2 cycles had been administered.
Criteria for DLT and MTD
DLT was defined as (a) grade 4 neutropenia or grade 3 or higher thrombocytopenia for > 5 days, (b) grade 3 or higher nonhematological toxicity (except mucositis for < 3 days, alopecia, fatigue, pain, or nausea), and (c) delay of > 1 week in the initiation of a subsequent course due to unresolved toxicity related to DRF-1042. MTD was defined as the highest dose level at which no more than 2 of 6 patients experienced DLT during the first course of therapy.
Analytical Methods
For pharmacokinetic analysis, whole-blood samples were collected before administration of DRF-1042 and 0.25, 0.5, 1, 2, 3, 4, 6, 8, 12, and 24 hours thereafter on days 1 and 12. Quantitation of DRF-1042 levels in other bodily fluids, such as ascites, was performed whenever possible. Concentrations of DRF-1042 for both lactone and total (lactone plus carboxylate) forms were determined by using a previously validated HPLC method.32 Briefly, detection was monitored by fluorescence set at excitation and emission wavelengths of 370 and 430 nm, respectively. The mobile phase was isocratic and consisted of acetonitrile/water (20:80) with 1% v/v triethanolamine. The pH of the mixture was adjusted to 5.5 with acetic acid. The flow rate was maintained at 1 mL/min. Standard curves, ranging between 4 and 2000 ng/mL, produced r2 values > 0.999. Quality control samples, run along with study samples for every standard curve, confirmed the accuracy and precision of the analytical determination, therefore supporting the validity of the pharmacokinetic disposition data of both forms of DRF-1042.
Pharmacokinetic Analysis
The plasma concentration versus time data were subjected to noncompartmental analyses using WinNonlin (version 3.1, Pharsight, NC). The peak plasma concentration was denoted as Cmax, and the time of occurrence of Cmax was denoted as tmax. The derived parameters included the following: AUC0-t is AUC from time zero to time t, where t denotes the last measurable point; AUC0-
is AUC extrapolated to infinity, using the summation of AUC0-t + Cn/ß, where Cn is the last measurable concentration and ß is the regression slope of the terminal data points; t1/2 is the terminal elimination half-life, calculated as the quotient of 0.693/ß; and R is the accumulation factor, calculated as the quotient of AUC0-t (day 12)/AUC0-t (day 1).
Statistical Analysis
Linear regression analysis was used to evaluate relationships between dose per square meter and AUC, and Pearson correlation coefficients were calculated. Spearman rank correlation coefficients were calculated between AUC and leukopenia/thrombocytopenia/diarrhea. The Wilcoxon signed-rank test was used to compare AUC (lactone) on days 1 and 12. Tumor response rate was given by
 |
 |
A p-value threshold of 0.05 was considered significant for both parametric and nonparametric tests.
|
RESULTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDiscussionACKNOWLEDGEMENTSREFERENCES |
|---|
|
Dose Escalation
Seventy-three assessable cycles of DRF-1042 were administered through 11 dose levels ranging from 1.5 to 270 mg/m2 (Table II). The median number of cycles per patient was 2 (range: 1-8).
|
Mortality
During this study, a 43-year-old male with gastric carcinoma and a history of gastrojejunostomy presented with hemetemesis 1 day after the end of second cycle at the 81-mg/m2 dose level for which he was given supportive care with blood products. The next day, his CBC showed myelosuppression for which he was put on broad-spectrum antibiotics with continued blood support. He developed abdominal distension the next day with peripheral circulatory failure and expired on the following day. Another patient, a 58-year-old male with colonic carcinoma, developed grade 4 diarrhea from the 7th day of the first cycle at 120 mg/m2. At the same time, he developed grade 3 leukopenia and thrombocytopenia. Treatment with IV fluids and oral antibiotics being of no avail, he was started on octreotide, injectable antibiotics, and growth factor. On day 16, CBC revealed grade 4 leukopenia. Despite supportive care, the patient expired 2 days later. A third patient, a 66-year-old female with ovarian carcinoma, developed grade 4 diarrhea on the 8th day of the first cycle at 120 mg/m2. Treatment with diphenoxylate and oral antibiotics showed no response. She was started on IV fluids from day 12. At the same time, it was found that the patient had developed neutropenia and thrombocytopenia, which was supported with blood products. Injectable antibiotics and octreotide were started from day 14. Diarrhea persisted with melena. The patient became dyspneic 3 days later and expired on the same day.
Dose-Limiting Toxicity
No DLT was observed in the first five dose levels (1.5-24 mg/m2). Dose-limiting hematological and nonhematological toxicities, including prolonged severe leukopenia and thrombocytopenia, diarrhea, and mucositis, were observed at higher doses (Table III), and subsequently, 120 mg/m2 was defined as the MTD for DRF-1042 administered orally for 5 consecutive days for 2 weeks every 3 weeks. The DLTs were not mutually exclusive, and some individuals experienced more than one dose-limiting event, often during the same course. At the dose recommended for phase II studies, 80 mg/m2, only 1 of 3 patients experienced a dose-limiting event.
|
Hematological Toxicity
Both severe leukopenia and thrombocytopenia were the principal hematological effects of treatment with DRF-1042 (Tables IV and V). Interpatient variability was observed at the various dose levels, but there was a significant relationship between the AUC (lactone) of DRF-1042 and the severity of leucopenia (p = 0.002). Grade 3 or 4 leukopenia and thrombocytopenia each occurred in 9 of 73 (12%) cycles. WBC and platelet count nadirs occurred between days 12 to 16 and days 12 to 21, respectively. No episodes of neutropenic fever occurred in this study. Most of the patients showed a recovery from leukopenia with G-CSF support.
|
|
DRF-1042 also affected RBCs. Although grade 3 or 4 anemia occurred in 8 (10%) cycles (data not shown), they were satisfactorily treated with packed RBC transfusions.
Gastrointestinal Toxicity
Gastrointestinal toxicities were the principal nonhematological toxic effect of DRF-1042. These consisted of nausea, vomiting, stomatitis, and various degrees of diarrhea. The frequency and severity of diarrhea are summarized in Table VI. Although interpatient susceptibility was substantial, there was a significant relationship between the AUC (lactone) of DRF-1042 and the severity of diarrhea (p = 0.005). Grade 3 or 4 diarrhea occurred in 5 (7%) cycles. The median time to onset of diarrhea was 7 days from day 1 of drug administration (range: 2-8). Loperamide hydrochloride, diphenoxylate, atropine sulfate, and octreotide were all ineffective in reducing the severity or duration in most patients with grade 3 or 4 diarrhea.
|
Nausea and vomiting were brief and usually noted in the peritreatment period. Although grade 3 or 4 nausea occurred in 12 (17%) courses and grade 3 vomiting in 5 (7%) courses, they could be circumvented with serotonin inhibitors and parenteral hydration. Grade 3 or 4 stomatitis occurred in 4 (5%) cycles.
Miscellaneous Toxicities
Grade 1 or 2 alopecia occurred in 24 (32%) cycles. The susceptibility to hair loss appeared quite varied. Other possible toxicities included grade 1 peripheral sensory neuropathy (1 patient) and transient alterations in hepatic and renal function tests (37 and 6 cycles, respectively). Hemorrhagic cystitis was observed in 1 patient at 36 mg/m2. Ultrasound abdomen in this patient revealed left hydronephrosis and left proximal ureteric dilatation. There were no identifiable drug interactions for DRF-1042.
Pharmacokinetics
Both forms of DRF-1042 were rapidly absorbed, as evident by the plasma concentration versus time curves on days 1 and 12 (Figure 2). DRF-1042 plasma levels were measurable even at the starting dose of 1.5 mg/m2. Peak concentrations were achieved within 0.25 to 3 hours for the lactone form and within 2 to 6.5 hours for the total form. Over a wide dose range of 120-fold, the absorption and disposition pattern of DRF-1042 appeared to be dose independent. It also appeared that the pharmacokinetic disposition of DRF-1042 was not altered by repeated dosing (Tables VII and VIII). Extrapolation of AUC was not performed in most patients because of limited number of data points available to accurately estimate terminal elimination. This was more often the case for the total form than the lactone form. The mean terminal half-life of the lactone form and the total form was 8.8 hours (range: 7.4-10.4 h) and 21.1 hours (range: 17-25.5 h), respectively. The t1/2 values on days 1 and 12 were similar.
|
|
|
AUC and Cmax increased with increasing doses from 1.5 to 180 mg/m2 (Figures 3 and 4). Significant dose versus AUC relationships were observed on both day 1 (p: lactone, 0.0001; total, 0.00002) and day 12 (p: lactone, 0.006; total, 0.0008), irrespective of the form tested. AUC (lactone) values were consistently higher on day 12 compared with day 1 (p = 0.004). There was modest accumulation of the lactone form on day 12 (1.6-fold), while the total form accumulated by 3.3-fold.
|
|
Efficacy
Thirteen patients (52%) received three cycles or more of DRF-1042. Eight of 12 (67%) evaluable patients had therapeutic responses (Table IX). The remainder was not evaluable because they did not complete two courses of therapy. Four patients demonstrated objective antitumor responses. A 46-year-old male with renal cell carcinoma (RCC) experienced a complete response (CR) of left supraclavicular lymph node metastasis following treatment with eight courses of DRF-1042 at a dose range of 81 to 270 mg/m2 (Figure 5). DRF-1042 was then discontinued, and the patient remained free of disease for more than 10 months. In another patient, a 21-year-old male with osteosarcoma and metastasis to left fourth rib treated with eight courses of DRF-1042 at a dose range of 120 to 180 mg/m2, CR was observed that lasted 6 weeks (Figure 6). Two partial responses (PRs) were documented in 1 patient with osteosarcoma treated at 54 mg/m2 and then 81 mg/m2 (74% decrease in pleural metastasis) and 1 patient with breast cancer treated at 180 mg/m2 and then 120 mg/m2 (> 50% decrease of primary tumor). The osteosarcoma and the breast cancer patient remained on PR for 12 and 21 weeks, respectively. Four patients had disease stabilization. This included 1 patient each with RCC, soft tissue sarcoma, gastric carcinoma, and histiocytoma. These responses lasted a median of 18.5 weeks (range: 17-20 weeks). Four patients were discontinued due to disease progression. All objective responses to DRF-1042 occurred at higher doses (i.e., 81-270 mg/m2), which suggests a dose-effect relationship.
|
|
|
|
Discussion |
|---|
|
TOPABSTRACTMETHODSRESULTSDiscussionACKNOWLEDGEMENTSREFERENCES |
|---|
Tissue culture and human xenograft data confirm the advantage of prolonged dosing for CPTs.36-38 Hochster et al39 showed that prolonged topotecan infusion in humans caused sustained depletion of topo-I, which may be an important consideration in the clinical use of topo-I inhibitory agents. Houghton et al36,37 have demonstrated increased efficacy with prolonged exposure to topotecan or irinotecan in a variety of xenograft models. On this basis, they advocated a protracted schedule of administration (i.e., daily for 5 days over 2 consecutive weeks with cycles repeated every 3 weeks). DRF-1042 was highly active in this schedule in human colon cancer and pediatric rhabdomyosarcoma models. In a report comparing the clinical pharmacodynamics of four different schedules of oral topotecan (daily x 5, every 21 days; daily x 5 x 2, every 21 days; bid x 10, every 21 days; and bid x 21, every 28 days), the total AUC per course was relatively consistent regardless of the schedule. In contrast, toxicity seemed to be related to schedule rather than to AUC, with myelosuppression and intestinal side effects dose limiting on shorter and protracted schedules, respectively. There was no apparent difference in antitumor activity among these four schedules.40
This phase I study evaluated the novel CPT derivative, DRF-1042, administered orally in a daily x 5 x 2 schedule, every 21 days, to patients with refractory solid tumors. The demography of patients enabled gauging the toxicity profile and pharmacokinetics across 16 different tumor types.
The toxicity profile of DRF-1042 was similar to other CPTs with myelosuppression, primarily neutropenia, and diarrhea being the DLTs. The cause of DRF-1042-induced diarrhea may possibly be a local effect of DRF-1042 on the intestinal mucosa (e.g., disturbance of the gastrointestinal flora or direct cytotoxicity to enterocytes).
Pharmacokinetic results showed that DRF-1042 possesses a long terminal half-life, which could be beneficial by prolonging exposure of tumor cells in vivo. This long half-life may account for the sustained cytotoxic concentrations of DRF-1042. Interestingly, DRF-1042 half-life seems longer than that of topotecan and CPT-11, the two CPT analogs currently on the market. It is also of interest that DRF-1042 half-life is longer in humans than in either mice or rats. The pharmacokinetics of the compound support once-daily administration. Moderate accumulation of the lactone/total forms does not appear to pose an issue, as observed from the toxicity profile. Measurable quantities of DRF-1042 were detected in the ascitic fluid of some patients. Although this could not be directly correlated with the toxicity profile, exclusion of patients with frank ascitis, pleural effusion, or pericardial effusion is recommended for phase II trials to eliminate the possibility of toxicities resulting from accumulation of the drug.
The strong correlation between DRF-1042 lactone AUC and the degree of leukopenia and diarrhea is consistent with the lactone being the active form of the CPTs. It also supports the attempt to measure the unstable DRF-1042 lactone species in addition to the more easily quantitated total drug level. Whether or not there is a correlation between these pharmacokinetic parameters with antitumor activity remains to be established in phase II trials.
Of the 8 patients having therapeutic responses, 5 received more than six cycles of drug. CRs were seen in 1 patient each with renal cell carcinoma and osteosarcoma. One patient each with osteosarcoma and carcinoma breast had a PR. These responses are particularly noteworthy because these patients were refractory to conventional chemotherapy. The suggested dose-response relationship needs confirmation in further trials.
Several tumor cell lines with BCRP overexpression possess cross-resistance to CPTs.41-44 Lack of BCRP specificity may explain both the broadness of activity of DRF-1042 as well as its better in vivo activity. Maximizing the clinical use of DRF-1042 will depend on developing preclinical models that define the mechanisms of activity and cellular resistance, as well as conducting appropriate clinical trials to test the hypotheses generated by these models.
On one hand, the total incidence of DLTs observed during the first cycle was eight among 25 patients (Table III). In addition, all DLTs were observed at higher doses (36-180 mg/m2). On the other hand, the total incidence of responses was eight among 25 patients (Table IX). Also, all objective responses occurred at higher doses (81-270 mg/m2). The observed balance between safety and efficacy with the chosen schedule needs further evaluation. If this schedule proves to be effective in solid tumors, it should be compared with other schedules to determine the optimal schedule for DRF-1042 as a single agent. Once the antitumor efficacy and the optimal schedule of DRF-1042 are defined, combination studies with other antineoplastic agents need to be performed to fully explore the clinical utility of this compound.
Since it is documented that there is a trend for more severe neutropenia in patients heavily pretreated with myelosuppressive therapies compared with minimally pretreated patients,45 it will be of interest to characterize the toxicity profile of DRF-1042 in such a population in phase II trials. The nonhematologic toxicities, particularly the gastrointestinal toxic effects, also need further clarification.
In summary, the MTD of DRF-1042 is 120 mg/m2 when administered orally for 5 consecutive days each week for 2 consecutive weeks, with myelosuppression and diarrhea being the DLTs. The recommended dose for phase II trials is 80 mg/m2, using the chosen schedule in this trial. The impressive anticancer activity described in this study needs to be defined further in phase II trials now under way at multiple sites in India.
|
ACKNOWLEDGEMENTS |
|---|
|
TOPABSTRACTMETHODSRESULTSDiscussionACKNOWLEDGEMENTSREFERENCES |
|---|
|
FOOTNOTES |
|---|
Revised version accepted March 22, 2004.
|
REFERENCES |
|---|
|
TOPABSTRACTMETHODSRESULTSDiscussionACKNOWLEDGEMENTSREFERENCES |
|---|
1. Wall ME, Wani MC, Cook CE, Palmer KH, McPhail AT, Lim GA: Plant antitumor agents: the isolation and structure of camptothecin, a novel alkaloid leukemia and tumor inhibitor from Camptotheca acuminata. J Am Chem Soc 1966;88: 3888-3890.[CrossRef]
2. Li LH, Fraser TJ, Olin EJ, Bhuyan BK: Action of camptothecin on mammalian cells in culture. Cancer Res 1972;32: 2643-2650.
3. Drewinko B, Freireich EJ, Gottlieb JA: Lethal activity of camptothecin sodium on human lymphoma cells. Cancer Res 1974;32: 747-750.
4. Gallo RC, Whang-Peng J, Adamson RH: Studies on the antitumor activity, mechanism of action, and cell cycle effects of camptothecin. J Natl Cancer Inst 1971;46: 789-795.
5. Gottlieb JA, Guarino AM, Call JB, Oliviero VT, Block JB: Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC-100880). Cancer Chemother Rep 1970;54: 461-470.[Web of Science][Medline] [Order article via Infotrieve]
6. Gottlieb JA, Luce JK: Treatment of malignant melanoma with camptothecin (NSC-100880). Cancer Chemother Rep 1972;56: 103-105.[Web of Science][Medline] [Order article via Infotrieve]
7. Moertel CG, Schutt AJ, Reitmeier RJ, Hahn RG: Phase II study of camptothecin (NSC-100880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 1972;56: 95-101.[Web of Science][Medline] [Order article via Infotrieve]
8. Muggia FM, Creaven PJ, Hansen HH, Cohen MH, Selawry OS: Phase I clinical trial of weekly and daily treatment with camptothecin (NSC-100880): correlation with preclinical studies. Cancer Chemother Rep 1972;56: 515-521.[Web of Science][Medline] [Order article via Infotrieve]
9. Creaven PJ, Allen LM, Muggia FM: Plasma camptothecin (NSC-100880) levels during a 5-day course of treatment: relation to dose and toxicity. Cancer Chemother Rep 1972;56: 573-578.[Web of Science][Medline] [Order article via Infotrieve]
10. Schaeppi V, Fleischman RW, Cooney DA: Toxicity of camptothecin (NSC-100880). Cancer Chemother Rep 1974;58: 25-36.
11. Giovanella BC, Stehlin JS, Wall ME, et al: DNA topoisomerase I-targeted chemotherapy of human colon cancer xenografts. Science 1989;246: 1046-1048.
12. Hsiang YH, Liu LF, Hochster H, et al: Levels of DNA topoisomerase I and II in human colorectal carcinoma and normal colonic mucosa [abstract]. Proc Am Assoc Cancer Res 1988;29: 172.
13. Potmesil H, Hsiang YH, Liu LF, et al: Topoisomerase I and topoisomerase II levels in high and low grade lymphomas [abstract]. Proc Am Assoc Cancer Res 1988;29: 176.
14. Horwitz SB, Horwitz MS: Effects of camptothecin on the breakage and repair of DNA during the cell cycle. Cancer Res 1973;33: 2834-2836.
15. Spataro A, Kessel D: The effects of camptothecin on DNA. Biochim Biophys Acta 1973;331: 194-201.[Medline] [Order article via Infotrieve]
16. Horwitz SB, Chang CK, Grollman AP: Studies on camptothecin: I. Effects on nucleic acid and protein synthesis. Mol Pharmacol 1971;7: 632-644.
17. Hsiang YH, Hertzberg R, Hecht S, Liu LF: Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. J Biol Chem 1985;260: 14873-14878.
18. Hsiang YH, Liu LF: Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. Cancer Res 1988;48: 1722-1726.
19. Wang JC: DNA topoisomerases. Annu Rev Biochem 1985;54: 665-697.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
20. Liu LF: DNA topoisomerase poisons as antitumor drugs. Annu Rev Biochem 1989;58: 3511-3575.
21. Pommier Y: Eukaryotic DNA topoisomerase I: Genome gate-keeper and its intruders, camptothecins. Semin Oncol 1996;23(Suppl. 3): 3-10.[Web of Science][Medline] [Order article via Infotrieve]
22. Silchenmeyer WJ, Rowinsky EK, Donehower RC, Kaufmann SH: The current status of camptothecin analogs as antitumor agents. J Natl Cancer Inst 1993;85: 271-291.
23. Potmesil M: Camptothecins from bench research to hospital wards. Cancer Res 1994;54: 1431-1439.
24. Burris HA, Fields SM: Topoisomerase I inhibitors: an overview of the camptothecin analogs. Hematol Oncol Clin North Am 1994;8: 333-355.[Web of Science][Medline] [Order article via Infotrieve]
25. Hertzberg RP, Caranfa MJ, Holden KG, Jakas DR, Gallagher G, Mattern MR, et al: Modification of the hydroxy lactone ring of camptothecin: inhibition of mammalian topoisomerase I and biological activity. J Med Chem 1989;32: 715-717.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
26. Eng WK, Faucette L, Johnson RK, Sternglanz R: Evidence that the DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. Mol Pharmacol 1988;34: 755-760.[Abstract]
27. Jaxel C, Kohn KW, Wani MC, Wall ME, Pommier Y: Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. Cancer Res 1989;49: 1465-1469.
28. D'Arpa P, Liu LF: Topoisomerase-targeting antitumor drugs. Biochim Biophys Acta 1989;989: 163-177.[Medline] [Order article via Infotrieve]
29. Chen AY, Yu C, Potmesil M, Wall ME, Wani MC, Liu LF: Camptothecin overcomes MDR1-mediated resistance in human carcinoma cells. Cancer Res 1991;51: 6039-6044.
30. Simon R, Freidlin B, Rubinstein L, Arbuck SG, Collins J, Christian MC: Accelerated titration designs for phase I clinical trials in oncology. J Natl Cancer Inst 1997;89: 1138-1147.
31. World Health Organization: The WHO Handbook for Reporting Results for Cancer Treatment. Geneva, Switzerland: World Health Organization, 1979.
32. Upreti VV, Mamidi RNVS, Katneni K, Srinivas NR: Quantitative determination of DRF-1042 in human plasma by HPLC: validation and application in clinical pharmacokinetics. Biomed Chromatogr 2003;17: 385-390.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
33. Hsiang YH, Lihou M, Liu LF: Arrest of replication forks by drug-stabilized topoisomerase I-DNA cleavable complexes as a mechanism of cell killing by camptothecin. Cancer Res 1989;49: 5077-5082.
34. Zhang H, D'Arpa P, Liu LF: A model for tumor cell killing by topoisomerase poisons. Cancer Cells 1990;2: 23-27.[Web of Science][Medline] [Order article via Infotrieve]
35. Pommier Y, Leteurtre F, Fesen MR, Fujimori A, Bertrand R, Solary E, et al: Cellular determinants of sensitivity and resistance to DNA topoisomerase inhibitors. Cancer Invest 1994;12: 530-543.[Web of Science][Medline] [Order article via Infotrieve]
36. Houghton P, Cheshire P, Hallman J, Lutz L, Friedman H, Danks M, et al: Efficacy of topoisomerase I inhibitors, topotecan and irinotecan, administered at low dose levels in protracted schedules to mice bearing xenografts of human tumors. Cancer Chemother Pharmacol 1995;36: 393-403.[Web of Science][Medline] [Order article via Infotrieve]
37. Houghton P, Stewart C, Zamboni W, Thompson J, Luo X, Houghton J: Schedule-dependent efficacy of camptothecins in models of human cancer. Ann NY Acad Sci 1996;803: 188-201.[Web of Science][Medline] [Order article via Infotrieve]
38. Zamboni W, Stewart C, Thompson J, Santana V, Cheshire P, Richmond L, et al: Relationship between topotecan systemic exposure and tumor response. J Natl Cancer Inst 1998;90: 505-511.
39. Hochster H, Liebes L, Speyer J, Sorich J, Taubes B, Oratz R, et al: Effect of prolonged topotecan infusion on topoisomerase 1 levels: a phase I and pharmacodynamic study. Clin Cancer Res 1997;3: 1245-1252.[Abstract]
40. Gerrits CJ, Schellens JH, Burris H, Eckhardt JR, Planting AS, van der Burg ME, et al: A comparison of clinical pharmacodynamics of different schedules of oral topotecan. Clin Cancer Res 1999;5: 69-75.
41. Yang CH, Schneider E, Kuo ML, Volk EL, Rocchi E, Chen YC: BCRP/MXR/ABCP expression in topotecan-resistant human breast carcinoma cells. Biochem Pharmacol 2000;60: 831-837.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
42. Kawabata S, Oka M, Shiozawa K, Tsukamoto K, Nakatomi K, Soda H, et al: Breast cancer resistance protein directly confers SN-38 resistance of lung cancer cell lines. Biochem Biophys Res Commun 2001;280: 1216-1223.[CrossRef][Web of Science][Medline] [Order article via Infotrieve]
43. Schellens JH, Maliepaard M, Scheper RJ, Scheffer GL, Jonker JW, Smit JW, et al: Transport of topoisomerase I inhibitors by the breast cancer resistance protein: potential clinical implications. Ann NY Acad Sci 2000;922: 188-194.[Web of Science][Medline] [Order article via Infotrieve]
44. Maliepaard M, van Gastelen MA, de Jong LA, Pluim D, van Waardenburg RC, Ruevekamp-Helmers MC, et al: Overexpression of the BCRP/MXR/ABCP gene in a topotecan-selected ovarian tumor cell line. Cancer Res 1999;59: 4559-4563.
45. Rowinsky EK, Grochow LB, Hendricks CB, Ettinger DS, Forastiere AA, Hurowitz LA, et al: Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. J Clin Oncol 1992;10: 647-656.
CiteULike 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  A. Chatterjee, R. Digumarti, K. Katneni, V. V. Upreti, R. N. V. S. Mamidi, R. Mullangi, A. Surath, M. L. Srinivas, S. Uppalapati, S. Jiwatani, et al. Safety, Tolerability, and Pharmacokinetics of a Capsule Formulation of DRF-1042, a Novel Camptothecin Analog, in Refractory Cancer Patients in a Bridging Phase I Study J. Clin. Pharmacol., April 1, 2005; 45(4): 453 - 460. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
