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C Erlichman

Publications and source records attributed to C Erlichman.

At least 19 recordsLinked to original sources
PubMed2005

Phase I-II trial of ONYX-015 in combination with MAP chemotherapy in patients with advanced sarcomas.

ONYX-015 is a provisionally replication competent adenovirus with oncolytic activity in cells with malfunctioning p53. Sarcomas represent a rational target for this approach given the high frequency of p53 mutations (40-75%) and MDM-2 amplification (10-30%). We, therefore, undertook a phase I/II study of ONYX-015, days 1-5 every month administered intratumorally under radiographic guidance, in combination with MAP (mitomycin-C, doxorubicin, cisplatin) chemotherapy in patients with advanced sarcoma. Six patients were treated. Injected lesions included liver metastases in four patients and chest wall metastases in two patients. Sarcoma histologies were gastrointestinal stromal tumors (GIST, two patients), leiomyosarcoma (two patients), liposarcoma (one patient), and malignant peripheral nerve sheath tumor (1 patient). Dose escalation was performed from 10(9) plaque forming units (PFU)/dose (total dose of 5 x 10(9) PFU/cycle) to 10(10) PFU/dose (total dose of 5 x 10(10) PFU/cycle) without dose-limiting toxicity being encountered. Immunohistochemistry of the metastatic lesions prior to treatment showed that five out of six patients were positive for p53, while two patients also had mdm-2 overexpression. Adenoviral replication was detected in two out of six patient biopsies on day 5 of the first cycle, by in situ hybridization (ISH). Both patients were treated at the highest dose level. ONYX-015 viral DNA was detected by quantitative PCR in the plasma of 5/6 patients on day 5 of the first cycle, and up to day 12 (7 days after the last viral dose) in one patient who had extended sampling for viral kinetics performed, suggesting viral replication in sarcoma tissue. One patient with p53 mutation and MDM-2 amplification achieved a partial response to treatment that lasted 11 months. In conclusion, intratumoral administration of ONYX-015 in combination with MAP chemotherapy is well tolerated with no significant toxicity due to ONYX-015 being encountered. Detection of viral DNA in post treatment tumor specimens by ISH and detection of the ONYX-015 genome in the peripheral blood by quantitative PCR, up to 7 days after the last viral dose provide evidence for adenoviral replication. There was evidence of antitumor activity in one out of six patients. Further investigation of this approach in patients with recurrent sarcomas is warranted.

Adenoviridae↗
PubMed2005

A phase I study of 153Sm-EDTMP with fixed high-dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma.

Despite response rates of 30% after high-dose chemotherapy with autologous hematopoietic stem cell transplant, patients with multiple myeloma are not cured. 153Samarium ethylenediaminetetramethylenephosphonate (153Sm-EDTMP; Quadramet) is a short-range, beta-emitting therapeutic radiopharmaceutical with avid skeletal uptake. In total, 12 patients were treated with escalating doses of 153Sm-EDTMP (N=3/group; 6, 12, 19.8, and 30 mCi/kg) and a fixed dose of melphalan (200 mg/m(2)). No dose limiting toxicity was seen. To better standardize the marrow compartment radiation dose, the study was modified such that an additional six patients were treated at a targeted absorbed radiation dose to the red marrow of 40 Gy based on a trace labeled infusion 1 week prior to the therapy. Despite rapid elimination of unbound radiopharmaceutical via kidneys and bladder, no episodes of nephrotoxicity, hemorrhagic cystitis, or delayed radiation nephritis were observed with a median follow-up of 31 months (range 8.5-44). Median times to ANC>0.5 and platelet >20 x 10(6)/l were 12 and 11 days, respectively, with no graft failures. Overall response rate was 94% including seven very good partial responses and five complete responses. Addition of 153Sm EDTMP to melphalan conditioning appears to be safe, well-tolerated and worthy of further study.

Adult↗
PubMed2003

The Hsp90 chaperone complex as a novel target for cancer therapy.

BACKGROUND: Heat shock protein 90 (Hsp90) is responsible for chaperoning proteins involved in cell signaling, proliferation and survival. 17-allylamino-17-demethoxygeldanamycin (17-AAG) is an anticancer agent currently in phase I trials in the USA and UK. It represents a class of drugs, the benzoquinone ansamycin antibiotics, capable of binding and disrupting the function of Hsp90, leading to the depletion of multiple oncogenic client proteins. MATERIALS AND METHODS: Studies were identified through a PubMed search, review of bibliographies of relevant articles and review of abstracts from national meetings. RESULTS: Preclinical studies have demonstrated that disruption of many client proteins chaperoned by Hsp90 is achievable and associated with significant growth inhibition, both in vitro and in tumor xenografts. Following an overview of the mechanism of action of ansamycin antibiotics and the pathways they disrupt, we review the current clinical status of 17-AAG, and discuss future directions for combinations of traditional antineoplastics with 17-AAG. CONCLUSIONS: 17-AAG represents a class of drugs capable of affecting multiple targets in the signal transduction pathway involved in tumor cell proliferation and survival. Early results from phase I studies indicate that 17-AAG administration results in an acceptable toxicity profile while achieving in vivo disruption of client proteins.

Animals↗
PubMed2002

A phase I study of sequential irinotecan and 5-fluorouracil/leucovorin.

BACKGROUND: Irinotecan (CPT-11) and 5-fluorouracil (5-FU)/leucovorin are active agents in colorectal cancer. A sequence-dependent synergism of SN-38 followed by 5-FU/leucovorin in vitro led us to conduct a phase I trial of CPT-11 followed by 5-FU/leucovorin to determine the maximum tolerated dose (MTD) and toxicities of this regimen and to obtain preliminary indications of its activity in patients with advanced solid tumors. PATIENTS AND METHODS: Fifty-six patients were enrolled in sequential cohorts to receive escalating doses of CPT-11 (90 min infusion) on day 1, followed by leucovorin 20 mg/m(2) (intravenous push) and 5-FU (90 min infusion) on days 2-5 of each 21-day cycle. RESULTS: A total of 347 treatment cycles (median 4, range 1-25) were administered. Dose-limiting toxicities were diarrhea, neutropenia and fatigue. Nine patients with colorectal cancer and one with gastric cancer had partial or minor responses. Eight of the 10 had prior chemotherapy. CONCLUSIONS: CPT-11 and 5-FU/leucovorin, as constituents of this novel mechanism-based schedule, have promising activity in patients who have received prior chemotherapy. The recommended phase II/III starting doses are CPT-11 275 mg/m(2) over 90 min on day 1, and 5-FU 400 mg/m(2) plus leucovorin 20 mg/m(2) on days 2-5 every 21 days. This combination can be administered safely to this schedule if there is strict adherence to the 90 min infusion time for both CPT-11 and 5-FU.

Adult↗
PubMed2001

The HER tyrosine kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10-hydroxycamptothecin and topotecan by inhibiting breast cancer resistance protein-mediated drug efflux.

Because the activities of HER family members are elevated and/or aberrant in a variety of human neoplasms, these cell surface receptors are receiving increasing attention as potential therapeutic targets. In the present study, we examined the effect of combining the HER family tyrosine kinase inhibitor CI1033 (PD 183805) with the topoisomerase (topo) I poison 7-ethyl-10-hydroxycamptothecin (SN-38), the active metabolite of irinotecan, in a number of different cell lines. Colony-forming assays revealed that the antiproliferative effects of simultaneous treatment with CI1033 and SN-38 were synergistic in T98G glioblastoma cells and HCT8 colorectal carcinoma cells, whereas sequential treatments were additive at best. In additional studies examining the mechanistic basis for these findings in T98G cells, immunoblotting revealed that the inhibitory effects of CI1033 on epidermal growth factor receptor autophosphorylation were unaffected by SN-38. Likewise, CI1033 had no effect on topo I polypeptide levels, localization, or activity. Nonetheless, CI1033 markedly enhanced the number of covalent topo I-DNA complexes stabilized by SN-38 or the related agent topotecan (TPT). Analysis of intracellular SN-38 levels by high-performance liquid chromatography and intracellular TPT levels by flow microfluorometry revealed that CI1033 increased the steady-state accumulation of SN-38 and TPT by 9.4 +/- 1.9- and 1.8 +/- 0.2-fold, respectively. Further evaluation revealed that the initial rate of TPT uptake was unaffected by CI1033, whereas the rate of efflux was markedly diminished. Additional studies demonstrated that T98G and HCT8 cells express the breast cancer resistance protein (BCRP), a recently cloned ATP binding cassette transporter. Moreover, CI1033 enhanced the uptake and cytotoxicity of SN-38 and TPT in cells transfected with BCRP but not empty vector. Conversely, CI1033 accumulation was diminished in cells expressing BCRP, suggesting that CI1033 is a substrate for this efflux pump. These results indicate that CI1033 can modulate the accumulation and subsequent cytotoxicity of two widely used topo I poisons in cells that have no history of previous exposure to these agents.

ATP Binding Cassette Transporter, Subfamily G, Mem↗
PubMed2001

Limited sampling models for CPT-11, SN-38, and SN-38 glucuronide.

PURPOSE: We developed limited sampling models (LSMs) for predicting the area under the curve (AUC) of irinotecan (CPT-11) and its metabolites SN-38 and SN-38 glucuronide (SN-38G). PATIENTS AND METHODS: Regression models were developed based on data from a phase I clinical trial involving 34 patients with advanced solid tumor malignancies who received CPT-11 as a 90-min infusion on an every 3-week dosing schedule. Multiple stepwise regression procedures were supplemented by all possible subsets regression analysis. Alternative clinically based and empirically derived LSMs were determined via model validation assessment including bootstrap simulation testing. RESULTS: The best LSMs for CPT-11 AUC included concentrations recorded at the end of infusion and 4 h later with an option to include a blood draw at 7.5 h from infusion start. For SN-38 and SN-38G AUC, optimal LSMs included the additional metabolite concentration at 48 h after infusion. The LSMs were able to predict most patient AUC values to within 10% of the true value. CONCLUSION: CPT-11 AUC can be modeled with acceptable accuracy using only two or three plasma concentration time-points. A variety of LSM alternatives provided comparable accuracy in predicting AUC. Given the wide variety of LSM alternatives, clinical considerations and patient burden become more important performance parameters than statistical considerations for the choice of time-points in constructing LSMs.

Antineoplastic Agents, Phytogenic↗
PubMed2001

Phase I trial of gemcitabine and CPT-11 given weekly for four weeks every six weeks.

BACKGROUND: Our previous studies have shown that the in vitro cytotoxicity of gemcitabine and SN-38, the active metabolite of irinotecan (CPT-11), is synergistic in human tumor cell lines. PATIENTS AND METHODS: Twenty-four patients with solid tumors, refractory to standard chemotherapy or for whom no effective therapy existed (age range 31-74; 7 female, 17 male; ECOG PS 0 = 12, 1 = 11, 2 = 1), received gemcitabine and CPT-11 weekly for four weeks out of every six weeks. Fifty courses of treatment (median 2, range 1-8) were given through five dose levels of gemcitabine/CPT-11 (600/75, 800/75, 800/100, 1000/100, 1000/125 mg/m2). RESULTS: Grade 3 and 4 neutropenia occurred in eight and two patients, respectively. Grade 3 and 4 thrombocytopenia occurred in one and three patients, respectively. Hematologic toxicity resulted in > or = 2 missed doses of treatment in two out of six patients and was therefore dose limiting at gemcitabine 1000 mg/m2 and CPT-11 125 mg/m2. Grade 3 and 4 diarrhea occurred in two and one patients, respectively. Other moderate non-hematologic toxicities included alopecia, anorexia, fatigue, nausea, vomiting, and weight loss. CONCLUSIONS: The maximum tolerated dose for this study recommended for phase II testing is gemcitabine 1000 mg/m2 and CPT-11 100 mg/m2. A partial response was seen in transitional cell carcinoma.

Adult↗
PubMed2001

Phase I trial of sequential administration of raltitrexed (Tomudex) and 5-iodo-2'-deoxyuridine (IdUrd).

Raltitrexed (Tomudex) is a specific inhibitor of thymidylate synthase with clinical activity in colorectal cancer. The combination of raltitrexed and 5-iodo-2'-deoxyuridine (IdUrd, a cytotoxic pyrimidine analog) resulted in increased IdUrd incorporation into DNA and exhibited in vitro synergism against colon and bladder human carcinoma cell lines. We designed a phase I trial to determine the MTD, pharmacokinetics, and biologic effects of escalating doses of the combination of IdUrd given as a 24-hour infusion after a raltitrexed 15-minute infusion every three weeks. Thirty-four patients received 95 courses of raltitrexed and IdUrd at doses ranging from raltitrexed 1 mg/m2 and IdUrd 750 mg/m2 to raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. The median number of cycles administered was 2 (range 1-10). Dose limiting hematologic toxicity occurred at doses of raltitrexed 2.5 mg/m2 and IdUrd 10,400 mg/m2. In addition, we determined the mean plasma concentrations C(SS) of IdUrd, the iodouracil level at 22 hours and the IdUrd clearance. Raltitrexed did not appear to affect the pharmacokinetics of IdUrd in the dose range tested. The recommended phase II dose is raltitrexed 2 mg/m2 and IdUrd 10,400 mg/m2 repeated every three weeks. Evidence of potential antitumor activity was observed: 1 patient (with colon cancer) had a partial response while 15 others had stable disease.

Adult↗
PubMed2001

Phase I study of the matrix metalloproteinase inhibitor, BAY 12-9566.

BACKGROUND: Matrix metalloproteinases (MMPs) are involved in tumor invasion and metastasis and have been implicated in breast, ovarian, colorectal, and lung cancer growth. We undertook a phase I study of BAY 12-9566, an inhibitor of MMP-2, MMP-9, and MMP-3, in patients with solid tumors to determine its safety, pharmacokinetics, and effects on potential surrogate markers of biologic activity. PATIENTS AND METHODS: BAY 12-9566 was orally administered daily at four dose levels; 400 mg daily, 400 mg b.i.d., 400 mg t.i.d., and 800 mg b.i.d. Drug disposition was determined on days 1 and 29 with weekly trough levels measured during the first four weeks. Plasma vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and urinary pyridinoline and deoxypyridinoline crosslinks were determined at baseline, once weekly for four weeks, and then every four weeks. RESULTS: Thirteen patients were entered on trial. BAY 12-9566 was well tolerated, with only one grade 3 headache, one grade 3 anemia, one grade 3 thrombocytopenia, and no musculoskeletal effects. The median treatment duration was 57 days (range 7-560). Mean trough levels of BAY 12-9566 on day 28 ranged from 80.5 to 108.6 mg/l. Plasma trough levels were 1500-42,000-fold above the Ki's for MMP-2, MMP-3, and MMP-9 at the 800 mg p.o. b.i.d. dose level. There was no significant change in VEGF, bFGF, pyridinoline, and deoxypyridinoline crosslinks with BAY 12-9566 administration. CONCLUSIONS: The recommended dose for further testing is 800 mg p.o. b.i.d.

Adult↗
PubMed2001

Synergy of the protein farnesyltransferase inhibitor SCH66336 and cisplatin in human cancer cell lines.

The enzyme protein farnesyltransferase, which catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first farnesyltransferase inhibitors to undergo clinical testing. In the present study, we examined the effect of combining SCH66336 with several classes of antineoplastic drugs in various human tumor cell lines. Flow cytometry indicated that SCH66336 had no effect on the cell cycle distribution of treated cells. Nonetheless, colony-forming assays revealed that the antiproliferative effects of SCH66336 and 5-fluorouracil were less than additive. In contrast, the effects of SCH66336 and melphalan were additive. Moreover, the combination of SCH66336 + cisplatin produced antiproliferative effects that were additive or synergistic over a broad range of clinically achievable concentrations in A549 non-small cell lung cancer cells and T98G human glioblastoma cells, but less than additive in MCF-7 breast, HCT116 colon, or BxPC-3 pancreatic adenocarcinoma cells. Examination of the effect of drug sequencing in A549 cells revealed synergism when cells were exposed to SCH66336 and then cisplatin and antagonism when drugs were administered in the opposite order. The additive and synergistic effects resulted in enhanced apoptosis with the SCH66336 + cisplatin combination. Additional studies failed to show any effect of SCH66336 on the formation or removal of platinum-DNA adducts, raising the possibility that SCH66336 is affecting survival of cisplatin-treated cells downstream of the DNA lesions. These observations suggest that SCH66336 exhibits additive or synergistic effects when combined with cisplatin in a sequence- and cell line-dependent fashion. Additional preclinical and clinical study of this combination appears warranted.

Alkyl and Aryl Transferases↗
PubMed2000

A Phase I trial of the farnesyl transferase inhibitor SCH66336: evidence for biological and clinical activity.

Farnesyl protein transferase (FT), an enzyme that catalyzes the first step in the posttranslational modification of ras and a number of other polypeptides, has emerged as an important target for the development of anticancer agents. SCH66336 is one of the first FT inhibitors to undergo clinical testing. We report a Phase I trial to assess the maximum tolerated dose, toxicities, and biological effectiveness of SCH66336 in inhibiting FT in vivo. Twenty patients with solid tumors received 92 courses of escalating SCH66336 doses given orally twice a day (b.i.d.) for 7 days out of every 3 weeks. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and fatigue were dose-limiting at 400 mg of SCH66336 b.i.d. Moderate reversible renal insufficiency, secondary to dehydration from gastrointestinal toxicity, was also seen. Inhibition of prelamin A farnesylation in buccal mucosa cells of patients treated with SCH66336 was demonstrated, confirming that SCH66336 inhibits protein farnesylation in vivo. One partial response was observed in a patient with previously treated metastatic non-small cell lung cancer, who remained on study for 14 months. This study not only establishes the dose for future testing on this schedule (350 mg b.i.d.) but also provides the first evidence of successful inhibition of FT in the clinical setting and the first hint of clinical activity for this class of agents.

Adult↗
PubMed2000

Phase I and pharmacokinetic study of irinotecan and docetaxel in patients with advanced solid tumors: preliminary evidence of clinical activity.

PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m(2), 160/65 mg/m(2), 200/65 mg/m(2), and 200/75 mg/m(2)) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non-small-cell lung cancer, achieved partial remissions. CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m(2) and docetaxel 65 mg/m(2).

Adult↗
PubMed2000

Phase I and pharmacologic study of sequences of gemcitabine and the multitargeted antifolate agent in patients with advanced solid tumors.

PURPOSE: Multitargeted antifolate (MTA) is an investigational agent that, like gemcitabine, exhibits broad activity in solid tumors. A phase I trial of MTA and gemcitabine was undertaken, based on the demonstration of preclinical cytotoxic synergy. PATIENTS AND METHODS: Thirty-five patients (group I) received 164 courses (median, four; range, one to 14 courses) of treatment of gemcitabine at doses of 1,000 and 1,250 mg/m(2) on days 1 and 8 and MTA at doses of 200, 300, 400, 500, and 600 mg/m(2), given 90 minutes after gemcitabine on day 1. Courses were repeated every 3 weeks. Because the day 8 dose of gemcitabine was reduced or omitted in 57% of courses due to neutropenia, 21 patients (group II) were treated on an alternate schedule, with MTA administered on day 8 rather than day 1. This group received 85 treatment courses (median, four; range, one to 10 courses). RESULTS: The most common and dose-limiting toxicity was neutropenia. Other toxicities included nausea, fatigue, rash, and elevated hepatic transaminases. The maximum-tolerated dose was gemcitabine/MTA 1,000/500 mg/m(2) for group I and 1,250/500 mg/m(2) for group II. Thirteen objective responses were documented (colorectal cancer, n = 3; non-small-cell lung cancer, n = 3; cholangiocarcinoma, n = 2; ovarian carcinoma, n = 2; mesothelioma, n = 1; breast cancer, n = 1; and adenocarcinoma of unknown primary site, n = 1). Gemcitabine had no effect on the disposition of MTA. CONCLUSION: The gemcitabine/MTA combination is broadly active and warrants further evaluation. The sequence of gemcitabine administered on days 1 and 8 with MTA administered on day 8 is better tolerated and is recommended for further study at doses of gemcitabine/MTA 1,250/500 mg/m(2).

Adult↗
PubMed2000

Metastatic non-small cell lung carcinoma with involvement of extremity musculature: case report and review of the literature.

Hematogenous dissemination of non-small cell lung carcinoma (NSCLC) metastatic to skeletal musculature in the absence of osseous involvement is an infrequent occurrence. We retrospectively reviewed our institution's indexed database for patients evaluated from 1975 through 1997 who were diagnosed as having skeletal musculature metastases from NSCLC. Eight men and 2 women were identified (age range, 51-80 years at time of metastases). Four primary adenocarcinomas, 4 primary lung squamous cell carcinomas (SCCs), and 2 poorly differentiated primary NSCLCs were identified. Approximate tumor sizes ranged from 10 cm3 to 288 cm3. External-beam radiation therapy was used in 7 of 10 cases; complete surgical excision was performed in 3 cases. Patients with known neoplasm who have extremity pain and negative findings on bone scan should be evaluated for soft tissue tumor involvement because such findings significantly affect clinical management. One case of lung SCC metastatic to the quadratus femoris muscle in a 63-year-old man is discussed in detail.

Aged↗
PubMed2000

Phase I dose-finding and pharmacokinetic trial of irinotecan hydrochloride (CPT-11) using a once-every-three-week dosing schedule for patients with advanced solid tumor malignancy.

A Phase I study was performed to determine the maximum tolerated dose (MTD), toxicities, and pharmacokinetic profile of irinotecan (CPT-11) and its active metabolites when given on a once-every-3-week schedule. Thirty-four patients with advanced refractory solid malignancies were treated with CPT-11 (240-340 mg/m2) administered as a 90-min i.v. infusion every 3 weeks. Patients were divided into two groups: those with and those without prior abdominal/pelvic (AP) radiotherapy. Gastrointestinal toxicity (nausea, vomiting, and diarrhea) and hematological toxicity (leukopenia and neutropenia) were dose-limiting side effects. Other common toxicities included anorexia, asthenia, and acute cholinergic symptoms (abdominal cramps, diaphoresis, and lacrimation). For patients with no prior AP radiation therapy, the MTD was determined to be 320 mg/m2, whereas those with prior AP radiation therapy had a MTD of 290 mg/m2. Dose-proportional increases in the mean area under the concentration-time curves for CPT-11, SN-38, and SN-38G were not observed over the narrow dose range studied. Mean values of terminal phase half-life, clearance, terminal phase volume of distribution, and steady-state volume of distribution for CPT-11 were 12.4 +/- 1.8 h, 13.0 +/- 3.8 liters/h/m2, 234 +/- 83 liters/m2, and 123 +/- 38 liters/m2, respectively. The pharmacodynamic analyses indicated the strongest correlation to be between SN-38 area under the concentration-time curves and neutropenia (p = 0.60; P = 0.001). A total of five responses (one complete response and four partial responses) were observed in the cohort of 32 patients with previously treated metastatic colorectal carcinoma. In conclusion, gastrointestinal toxicity and hematological toxicity were the dose-limiting toxicities of CPT-11 when administered as a 90-min infusion every 3 weeks. In this trial, the recommended Phase II starting dose for patients with no prior AP radiation therapy was found to be 320 mg/m2; for patients with prior AP radiation, the recommended Phase II starting dose was 290 mg/m2. This once-every-3-week schedule has been incorporated into a Phase I trial of CPT-11 combined with 5-fluorouracil and leucovorin.

Adjuvants, Anesthesia↗
PubMed2000

Comparison of potential markers of farnesyltransferase inhibition.

Farnesyltransferase inhibitors (FTIs) were developed to target abnormal signaling pathways that are commonly activated in neoplastic cells. Five FTIs have recently undergone Phase I testing; and two are currently in Phase II clinical trials. As part of the development of these agents, there has been interest in determining their cellular effects in the clinical setting. Several approaches have been proposed, including measurement of FT enzymatic activity, evaluation of the processing of FT polypeptide substrates, and assessment of the accumulation of p21waf1. In the present study, a number of these assays have been compared in four cultured human neoplastic cell lines of different histology (A549, HCT116, BxPC-3, and MCF-7) after treatment with the nonpeptidomimetic FTI SCH66336 and the peptidomimetic inhibitor FTI-277. Immunoblotting studies failed to demonstrate a mobility shift in ras proteins or increased accumulation of p21waf1 after treatment with these agents. In contrast, drug-induced increases in the slower migrating, unprocessed species of the chaperone protein HDJ-2 and the intranuclear intermediate filament protein lamin A were detected in all four cell lines after treatment with either agent. Unprocessed forms of both polypeptides accumulated in noncycling as well as cycling cells. The precursor peptide that is present in prelamin A but absent from mature lamin A could be readily detected by immunohistochemistry in noncycling cells with a peptide-specific antiserum. Our results indicate that unprocessed HDJ-2 and prelamin A should be suitable markers of FT inhibition in clinical samples.

Alkyl and Aryl Transferases↗