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Purpose: Inhibiting survivin and Cdc2 (CDK1) has preclinical anti-leukemic activity. Terameprocol is a small molecule survivin and Cdc2/CDK1 inhibitor that was studied in a Phase I dose-escalation trial., Patients and Methods: Sixteen patients with advanced acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) were enrolled and 15 treated with Terameprocol in three dose cohorts intravenously three times per week for 2 weeks every 21 days., Results: Patients had AML (n = 11), chronic myelogeneous leukemia in blast phase (CML-BP, n = 2) and one each T-cell acute lymphoblastic leukemia (T-ALL) and MDS. Four, five and six patients were treated at the 1000, 1500 and 2200 mg Terameprocol dose cohorts respectively. Common related treatment emergent adverse events (TEAE) were grade 1 or 2 headache, transaminitis and pruritus, with one grade 4 serious AE (SAE) of pneumonia. No dose limiting toxicity (DLT) was observed, however, due to other observed grade 3 TEAE the recommended phase 2 dose (RP2D) was determined at 1500 mg 3×/week for 2 weeks of a 21-day cycle. Partial remission and transfusion independence in a CML-BP patient (1500 mg cohort) and hematological improvement in erythroid (HI-E) and platelet lineage (HI-P) in an AML patient were observed. Five AML patients had stable disease greater/equal to 2 months. Pharmacodynamic studies showed a reduction of CDK1 and phospho-AKT protein expression., Conclusion: Terameprocol can be safely administered to advanced leukemia patients, sufficient drug exposure was obtained and clinical activity and biomarker modulation were observed.

Background: 17-(Allylamino)-17-demethoxygeldanamycin (17-AAG) is a benzoquinone ansamycin that binds to and inhibits the Hsp90 family of molecular chaperones leading to the proteasomal degradation of client proteins critical in malignant cell proliferation and survival. We have undertaken a Phase 1 trial of CNF1010, an oil-in-water nanoemulsion of 17-AAG., Methods: Patients with advanced solid tumors and adequate organ functions received CNF1010 by 1-h intravenous (IV) infusion, twice a week, 3 out of 4 weeks. Doses were escalated sequentially in single-patient (6 and 12 mg/m(2)/day) and three-to-six-patient (≥25 mg/m(2)/day) cohorts according to a modified Fibonacci's schema. Plasma pharmacokinetic (PK) profiles and biomarkers, including Hsp70 in PBMCs, HER-2 extracellular domain, and IGFBP2 in plasma, were performed., Results: Thirty-five patients were treated at doses ranging from 6 to 225 mg/m(2). A total of 10 DLTs in nine patients (2 events of fatigue, 83 and 175 mg/m(2); shock, abdominal pain, ALT increased, increased transaminases, and pain in extremity at 175 mg/m(2); extremity pain, atrial fibrillation, and metabolic encephalopathy at 225 mg/m(2)) were noted. The PK profile of 17-AAG after the first dose appeared to be linear up to 175 mg/m(2), with a dose-proportional increase in C max and AUC0-inf. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects of CNF1010 at doses >83 mg/m(2)., Conclusion: The maximum tolerated dose was not formally established. Hsp70 induction in PBMCs and inhibition of serum HER-2 neu extracellular domain indicated biological effects. The CNF1010 clinical program is no longer being pursued due to the toxicity profile of the drug and the development of second-generation Hsp90 molecules.

Background: AT7519 is an inhibitor of multiple cyclin-dependent kinases (CDKs). Based on potent antitumor activity in preclinical models, a first-in-human clinical trial in refractory solid tumors investigated its safety, tolerability, pharmacokinetics (PK) and pharmacodynamics (PD)., Patients and Methods: AT7519 was administered in a '3 + 3' dose- escalation scheme on 5 consecutive days every 3 weeks to patients with advanced, refractory solid tumors. Samples to monitor AT7519 PK and PD were obtained., Results: Twenty-eight patients were treated at seven dose levels (1.8-40 mg/m(2)/day). At 40 mg/m(2)/day, one patient developed hypotension and ST segment elevation. At 34 mg/m(2)/day, dose-limiting toxic effects (DLTs) were QTc prolongation with one death (grade 5), fatigue (grade 4) and mucositis (grade 3). Electrocardiogram review suggested a dose-dependent increase in QTc and recruitment was discontinued without establishing a maximum tolerated dose. Four patients exhibited stable disease for >6 months and one had a prolonged partial response. PK profile revealed modest interpatient variation with linear exposure at increasing doses. Inhibition of markers of CDK activity was observed across the dose range and manifested in antiproliferative activity at a dose of 28 mg/m(2)., Conclusion: AT7519 elicited clinical and PD activity resulting from CDK inhibition at doses below the appearance of DLT of QTc prolongation.

Genomic profiling is beginning to extend beyond the many applications in discovery research toward direct medical applications that hold the promise of more precise and individualized health-care delivery. There are many barriers and challenges that still need to be overcome before 'Precision Medical Genomics' can deliver the promise of more informed patient care, not the least of which is the unmet need for a new conceptual framework for recovering, understanding and translating potentially useful information from a single genome. Although a wide spectrum of scientific strategies, bioinformatic approaches, IT tools and knowledge resources have been developed to support discovery research, the interpretive requirements for recovering clinically useful insights from an individual's genome are different in many ways from those of traditional research goals. In this study, we compare and contrast the fundamental conceptual differences that distinguish 'research' to discover generalized knowledge from 'search' to recover individualized knowledge. We also consider the merits of applying evidence-based medicine and traditional scientific methods when n=1, and consider an alternative perspective based on a translational engineering approach and intelligence for interpreting genomic information from an individual case. Although the general idea of biological intelligence-based knowledge recovery that we introduce here can be broadly applied for personal genomics across many indications in medicine, we make a case that the need for adopting such a paradigm is greatest for supporting the management of complex diseases, and particularly suited for supporting therapeutic decisions in medical oncology. Early concepts for designing and implementing this kind of 'BioIntelligence' solution will be discussed. We also review the anticipated challenges of implementing genomic analysis and biological intelligence-based solutions in the practice of medical oncology by discussing some of the related pragmatic considerations for deploying the first generation of a 'Precision Medical Genomics' solution that can evolve and improve over time.

Background: This randomized phase III study compared the overall survival (OS) of pemetrexed plus gemcitabine (PG) versus standard gemcitabine (G) in patients with advanced pancreatic cancer., Patients and Methods: Patients with unresectable locally advanced or metastatic pancreatic cancer and no prior systemic therapy (including 5-fluorouracil as a radiosensitizer) were randomized to receive either 1,250 mg/m(2) gemcitabine on days 1 and 8 plus pemetrexed 500 mg/m(2) after gemcitabine on day 8 (PG arm) of each 21-day cycle, or gemcitabine 1,000 mg/m(2) on days 1, 8 and 15 of each 28-day cycle (G arm)., Results: Five hundred and sixty-five patients with well-balanced baseline characteristics were randomly assigned (283 PG, 282 G). OS was not improved on the PG arm (6.2 months) compared with the G arm (6.3 months) (P=0.8477). Progression-free survival (3.9 versus 3.3 months; P=0.1109) and time to treatment failure (3 versus 2.2 months; P=0.2680) results were similar. Tumor response rate (14.8% versus 7.1%; P=0.004) was significantly better on the PG arm. Grade 3 or 4 neutropenia (45.1% versus 12.8%), thrombocytopenia (17.9% versus 6.2%), anemia (13.9% versus 2.9%), febrile neutropenia (9.9% versus 0.4%; all P <0.001) and fatigue (15% versus 6.6%; P=0.002) were significantly more common on the PG arm. Four treatment-related deaths occurred on the PG arm and none in the G arm., Conclusions: Pemetrexed plus gemcitabine therapy did not improve OS. Single-agent gemcitabine remains the standard of care for advanced pancreatic cancer.

Purpose: To determine whether addition of the farnesyltransferase inhibitor tipifarnib (Zarnestra, R115777; Johnson and Johnson Pharmaceutical Research and Development, Beerse, Belgium) to standard gemcitabine therapy improves overall survival in advanced pancreatic cancer., Patients and Methods: This randomized, double-blind, placebo-controlled study compared gemcitabine + tipifarnib versus gemcitabine + placebo in patients with advanced pancreatic adenocarcinoma previously untreated with systemic therapy. Tipifarnib was given at 200 mg bid orally continuously; gemcitabine was given at 1,000 mg/m(2) intravenously weekly x 7 for 8 weeks, then weekly x 3 every 4 weeks. The primary end point was overall survival; secondary end points included 6-month and 1-year survival rates, progression-free survival, response rate, safety, and quality of life., Results: Six hundred eighty-eight patients were enrolled. Baseline characteristics were well balanced between the two treatment arms. No statistically significant differences in survival parameters were observed. The median overall survival for the experimental arm was 193 v 182 days for the control arm (P =.75); 6-month and 1-year survival rates were 53% and 27% v 49% and 24% for the control arm, respectively; median progression-free survival was 112 v 109 days for the control arm. Ten drug-related deaths were reported for the experimental arm and seven for the control arm. Neutropenia and thrombocytopenia grade > or = 3 were observed in 40% and 15% in the experimental arm versus 30% and 12% in the control arm. Incidences of nonhematologic adverse events were similar in two groups., Conclusion: The combination of gemcitabine and tipifarnib has an acceptable toxicity profile but does not prolong overall survival in advanced pancreatic cancer compared with single-agent gemcitabine.

Background: Based on preclinical studies demonstrating that treatment with paclitaxel upregulates intratumoral thymidine phosphorylase (dTHdPase), which catalyzes the final step in the conversion of the oral fluoropyrimidine capecitabine to 5-fluorouracil (5-FU), as well as the overlapping spectra of activity for these agents, particularly in metastatic breast cancer, this phase I study evaluated the feasibility of administering capecitabine on an intermittent schedule in combination with paclitaxel in previously-treated patients with locally advanced or metastatic breast cancer. The study also sought to recommend doses for subsequent disease-specific studies, identify clinically significant pharmacokinetic interactions, and detect preliminary antitumor activity., Patients and Methods: Nineteen previously treated women with metastatic breast cancer whose prior treatment included neither paclitaxel or capecitabine received one hundred one courses of capecitabine and paclitaxel. Paclitaxel was administered as a three-hour intravenous (i.v.) infusion at a fixed dose of 175 mg/m2 and capecitabine was administered as 2 divided daily doses for 14 days followed by a seven-day rest period every 3 weeks. The dose of capecitabine was increased from a starting dose of 1650 mg/m2/d. The plasma sampling scheme in the first course permitted characterization of the pharmacokinetics of each agent given alone and concurrently to detect major pharmacokinetic interactions., Results: Palmar plantar erythrodysesthesia (hand foot syndrome) and neutropenia were the principal dose-limiting toxicities (DLT). Other toxicities included diarrhea and transient hyperbilirubinemia. Three of eight new patients treated with capecitabine 2000 mg/m2/d and paclitaxel 175 mg/m2 experienced DLT in the first course, whereas none of eleven new patients treated with capecitabine 1650 mg/m2/d and paclitaxel 175 mg/m2 developed DLT. Pharmacokinetic studies indicated that capecitabine did not grossly affect the pharmacokinetics of paclitaxel, and there were no major effects of paclitaxel on the pharmacokinetics of capecitabine and capecitabine metabolites. However, AUC values for the major 5-FU catabolite, fluorobeta-alanine (FBAL), were significantly lower in the presence of paclitaxel. Two complete and seven partial responses (56% response rate) were observed in sixteen patients with measurable disease; four of six patients whose disease was previously treated with high-dose chemotherapy and hematopoietic stem-cell support had major responses. Seven of nineteen patients had stable disease as their best response., Conclusions: Recommended combination doses of capecitabine on an intermittent schedule and paclitaxel are capecitabine 1650 mg/m2/d orally for 14 days and paclitaxel 175 mg/m2 i.v. every 3 weeks. The favorable preclinical interactions between capecitabine and paclitaxel, as well as the acceptable toxicity profile and antitumor activity in patients with metastatic breast cancer, support further clinical evaluations to determine an optimal role for the combination of capecitabine and paclitaxel in breast cancer and other relevant malignancies.

Purpose: 6-Hydroxymethylacylfulvene (HMAF; MGI 114; Irofulven) is a semisynthetic analogue of the mushroom toxin illudin S that has been shown to be a potent cytotoxic agent with an improved therapeutic index compared with its parent compound. The studies were conducted to evaluate the antitumor activity of MGI 114 as a single agent and in combination with topotecan against pediatric solid tumor cell lines and xenograft models., Materials and Methods: In vitro studies were designed to determine the cytotoxic potential of MGI 114 using the MTT assay and 13 pediatric tumor cell lines. In addition, combination in vitro studies were performed with MGI 114 and topotecan to generate isoeffect plots. Single agent and combination in vivo studies were also performed using MGI 114 against rhabdomyosarcoma and neuroblastoma xenograft models., Results: After a 1-hour exposure to MGI 114, the mean IC50 (+/-standard error of mean) for medulloblastoma, neuroblastoma, Ewing sarcoma/primitive neuroectodermal tumor, and rhabdomyosarcoma cell lines were 1.58+/-0.51, 1.60+/-0.82, 1.18+/-0.08, and 3.99+/-1.69 microg/mL, respectively. When tumor cells were exposed concurrently to MGI 114 and topotecan, evidence of synergy was observed in 10 of 12 (83%) cell lines. Single agent and combination in vivo studies with MGI 114 showed that this agent had substantial, and at times curative, antitumor activity against rhabdomyosarcoma and neuroblastoma xenograft tumors., Conclusions: These data suggest that MGI 114 has significant efficacy as a single agent in preclinical studies against pediatric tumors. In addition, based on previous reports and the results presented here, combining MGI 114 with topotecan appears to be an attractive approach to the treatment of pediatric malignancies. After completion of the pediatric phase I studies of MGI 114, consideration should be given to phase II single agent and phase I combination studies with a topoisomerase I inhibitor such as topotecan or irinotecan.

Shortening of telomeres along with an up-regulation of telomerase is implicated in the immortality of tumor cells. Targeting either telomeres or telomerase with specific compounds has been proposed as an anticancer strategy. Because telomerase activity and telomeres are found in normal cells, telomere or telomerase targeting agents could induce side effects in normal tissues. We evaluated the effects of telomere and telomerase interactive agents in human tumor and normal cell lines to try to determine the potential side effects those agents might induce in patients. Toxicity of the G-quadruplex interactive porphyrins (TMPyP4, TMPyP2) and azidothymidine (AZT) were tested using a cell-counting technique against normal human cell lines (CRL-2115 and CRL-2120, fibroblasts; NHEK-Ad, adult keratinocytes; CCL-241, small intestinal cells; NCM 460, colonic mucosal epithelial cells) and human tumor cell lines (MDA-MB 231 and Hs 578T, breast cancer; SK-N-FI, neuroblastoma; HeLa, cervix cancer; MIA PaCa-2, pancreatic cancer; HT-29 and HCT-116, colon cancer; DU 145, prostatic cancer cell line). Telomerase activity of these cell lines was measured by a non-PCR-based conventional assay. The effects of TMPgammaP2, TMPyP4, and AZT were also evaluated against normal human bone marrow specimens, using a granulocyte-macrophage colony-forming assay (CFU-GM). AZT showed very low cytotoxic effects against normal and tumor cell lines, with the IC50 values above 200 microM. The IC50 values for TMPyP2 and TMPyP4 in normal human cell lines were in the range of 2.9-48.3 microM and 1.7-15.5 microM, respectively, whereas in tumor cell lines the IC50 values were 11.4-53 microM and 9.0-28.2 microM, respectively. Within the tissue types, keratinocytes were more sensitive to TMPyP4 than fibroblasts, and small intestinal cells were more sensitive than colonic mucosal epithelial cells. The IC50 for TMPyP2 and TMPyP4 in the normal marrow colony-forming assays were 19.3 +/- 5.1 microM and 47.9 +/-1.0 microM, respectively. In conclusion, the in vitro cytotoxicity of the telomere interactive agent TMPyP4 is comparable in human tumor and normal cell lines, which indicates that TMPyP4 could have effects on normal tissues.

The activities of a series of camptothecin and nitidine derivatives that might interact with topoisomerase I were compared against yeast and cancer cell lines. Our findings reveal that structural modifications to camptothecin derivatives have profound effects on the topoisomerase I-drug poison complex in cells. Although the water-soluble anticancer agents topotecan and irinotecan are less active than the original structure, camptothecin, other derivatives or analogs with substitutions that increase compound solubility have also increased antifungal activities. In fact, a water-soluble prodrug appears to penetrate into the cell and release its active form; the resulting effect in complex with Cryptococcus neoformans topoisomerase I is a fungicidal response and also potent antitumor activity. Some of the compounds that are not toxic to wild-type yeast cells are extremely toxic to the yeast cells when the C. neoformans topoisomerase I target is overexpressed. With the known antifungal mechanism of a camptothecin-topoisomerase I complex as a cellular poison, these findings indicate that drug entry may be extremely important for antifungal activity. Nitidine chloride exhibits antifungal activity against yeast cells through a mechanism(s) other than topoisomerase I and appears to be less active than camptothecin analogs against tumor cells. Finally, some camptothecin analogs exhibit synergistic antifungal activity against yeast cells in combination with amphotericin B in vitro. Our results suggest that camptothecin and/or nitidine derivatives can exhibit potent antifungal activity and that the activities of camptothecin derivatives with existing antifungal drugs may be synergistic against pathogenic fungi. These new compounds, which exhibit potent antitumor activities, will likely require further structural changes to find more selective activity against fungal versus mammalian cells to hold promise as a new class of antifungal agents.

Purpose: To determine the maximum-tolerated dose (MTD) and pharmacologic behavior of ISIS 3521 (ISI 641A), an antisense phosphorothioate oligonucleotide to protein kinase C-alpha., Patients and Methods: Thirty-six patients with advanced cancer received 99 cycles of ISIS 3521 (0.15 to 6.0 mg/kg/d) as a 2-hour intravenous infusion administered three times per week for 3 consecutive weeks and repeated every 4 weeks. Plasma and urine sampling was performed during the first week of treatment and subjected to capillary gel electrophoresis to determine full-length antisense oligonucleotide in addition to chain-shortened metabolites., Results: Drug-related toxicities included mild to moderate nausea, vomiting, fever, chills, and fatigue. Hematologic toxicity was limited to thrombocytopenia (grade 1, four patients; grade 2, one patient; grade 3, one patient). There was no relationship between dose, maximum concentration of the drug (C(max)), or area under the plasma concentration versus time curve (AUC) and coagulation times or complement levels. Dose escalation was discontinued because of the attainment of peak plasma concentrations, which approached that associated with complement activation in primates. Two patients with non-Hodgkin's lymphoma who completed 17 and nine cycles of therapy achieved complete responses. The pharmacokinetic profile of ISIS 3521 revealed a short elimination half-life (18 to 92 minutes), as well as a dose-dependent decrease in clearance and dose-dependent increases in C(max), AUC, and elimination half-life., Conclusion: No dose-limiting toxicity of ISIS 3521 was identified, and clinical activity was observed. A short elimination half-life was identified, which suggests that alternate schedules with prolonged administration may be necessary for further clinical development.

Purpose: Because toxicities associated with chemotherapy and radiotherapy can adversely affect short- and long-term patient quality of life, can limit the dose and duration of treatment, and may be life-threatening, specific agents designed to ameliorate or eliminate certain chemotherapy and radiotherapy toxicities have been developed. Variability in interpretation of the available data pertaining to the efficacy of the three United States Food and Drug Administration-approved agents that have potential chemotherapy- and radiotherapy-protectant activity-dexrazoxane, mesna, and amifostine-and questions about the role of these protectant agents in cancer care led to concern about the appropriate use of these agents. The American Society of Clinical Oncology sought to establish evidence-based, clinical practice guidelines for the use of dexrazoxane, mesna, and amifostine in patients who are not enrolled on clinical treatment trials., Methods: A multidisciplinary Expert Panel reviewed the clinical data regarding the activity of dexrazoxane, mesna, and amifostine. A computerized literature search was performed using MEDLINE. In addition to reports collected by individual Panel members, all articles published in the English-speaking literature from June 1997 through December 1998 were collected for review by the Panel chairpersons, and appropriate articles were distributed to the entire Panel for review. Guidelines for use, levels of evidence, and grades of recommendation were reviewed and approved by the Panel. Outcomes considered in evaluating the benefit of a chemotherapy- or radiotherapy-protectant agent included amelioration of short- and long-term chemotherapy- or radiotherapy-related toxicities, risk of tumor protection by the agent, toxicity of the protectant agent itself, quality of life, and economic impact. To the extent that these data were available, the Panel placed the greatest value on lesser toxicity that did not carry a concomitant risk of tumor protection., Results and Conclusion: Mesna: (1) Mesna, dosed as detailed in these guidelines, is recommended to decrease the incidence of standard-dose ifosfamide-associated urothelial toxicity. (2) There is insufficient evidence on which to base a guideline for the use of mesna to prevent urothelial toxicity with ifosfamide doses that exceed 2.5 g/m(2)/d. (3) Either mesna or forced saline diuresis is recommended to decrease the incidence of urothelial toxicity associated with high-dose cyclophosphamide use in the stem-cell transplantation setting. Dexrazoxane: (1) The use of dexrazoxane is not routinely recommended for patients with metastatic breast cancer who receive initial doxorubicin-based chemotherapy. (2) The use of dexrazoxane may be considered for patients with metastatic breast cancer who have received a cumulative dosage of 300 mg/m(2) or greater of doxorubicin in the metastatic setting and who may benefit from continued doxorubicin-containing therapy. (3) The use of dexrazoxane in the adjuvant setting is not recommended outside of a clinical trial. (4) The use of dexrazoxane can be considered in adult patients who have received more than 300 mg/m(2) of doxorubicin-based therapy for tumors other than breast cancer, although caution should be used in settings in which doxorubicin-based therapy has been shown to improve survival because of concerns of tumor protection by dexrazoxane. (5) There is insufficient evidence to make a guideline for the use of dexrazoxane in the treatment of pediatric malignancies, with epirubicin-based regimens, or with high-dose anthracycline-containing regimens. Similarly, there is insufficient evidence on which to base a guideline for the use of dexrazoxane in patients with cardiac risk factors or underlying cardiac disease. (6) Patients receiving dexrazoxane should continue to be monitored for cardiac toxicity. Amifostine: (1) Amifostine may be considered for the reduction of nephrotoxicity in patients receiving cisplatin-based chemoth

Purpose: Tirapazamine (3-amino-1,2,4-benzotriazine 1,4-dioxide; SR 4233) is a bioreductive agent that exhibits relatively selective cytotoxicity towards cells under hypoxic conditions and can enhance the antitumor activity of many standard oncolytics. In the present study we examined the interaction between tirapazamine in vivo with paclitaxel and paraplatin in two- and three-way combination studies using the MV-522 human lung carcinoma xenograft model., Methods: Agents were administered as a single i.p. bolus, with tirapazamine being given 3 h prior to paclitaxel, paraplatin, or their combination. Tumor growth inhibition (TGI), final tumor weights, partial and complete responses, and time to tumor doubling were determined after drug administration., Results: Tirapazamine as a single agent was ineffective against this human lung tumor model. A substantial increase in TGI was seen in animals treated with the triple-agent regimen (tirapazamine-paclitaxel-paraplatin) compared to animals treated with double-agent regimens that did not include tirapazamine. The addition of tirapazamine to paclitaxel-paraplatin therapy resulted in a 50% complete response rate; there were no complete responses seen when only the paclitaxel-paraplatin combination was administered. Time to tumor doubling was also significantly improved with the addition of tirapazamine to the paclitaxel and paraplatin combinations. Tirapazamine did not increase the toxicity of paclitaxel, paraplatin, or their combinations as judged by its minimal impact on body weight and the fact that no toxic deaths were observed with tirapazamine-containing regimens., Conclusions: These results are important since recent studies have suggested that the combination of paclitaxel and paraplatin may be particularly active in patients with advanced stage non-small-cell lung cancer. Since tirapazamine can significantly improve efficacy, but does not appear to enhance the toxicity of paclitaxel and paraplatin, its evaluation in future clinical trials in combination with paclitaxel-paraplatin-based therapy appears warranted.

Human telomeres are guanine-rich regions (TTAGGG) located at the end of chromosomes that protect them against aberrant recombination and protect DNA from exonuclease degradation. Telomeres maintenance is performed by telomerase, a RNA-dependent DNA polymerase. Telomerase is over-expressed in a large number of cancers that have short telomeres whereas it is not expressed in somatic cells that have long telomeres. Therefore, this differential gives a rational for further evaluation of telomerase and telomeres as targets for identification of new anticancer drugs. Current strategies aim to identify new drugs with specific activity against telomerase and telomeres. In this review we will discuss the biological and clinical approaches as well as relevant tumor models for studying the biological effects of telomerase inhibition and telomere targeting in vitro and in vivo.

The purpose of this study was to evaluate the diblock copolymer poly(DL-lactide)-block-methoxy polyethylene glycol as an i.v. delivery vehicle for paclitaxel. Nude mice were implanted s.c. with fragments of MV-522 lung carcinomas and treated with paclitaxel on a daily x 5 schedule when tumors were approximately 5 x 5 mm in size. Cremophor paclitaxel or polymeric micellar paclitaxel were given i.p. or i.v. at the maximum tolerated dose (Cremophor paclitaxel MTD: 20 mg/kg/day i.v. or i.p.; micellar paclitaxel MTD: 25 mg/kg/day i.v. or 100 mg/kg/day i.p.). The tumors were measured using callipers during the experiment and accurately weighted at the end. Two biodistribution studies were carried out. In one study, the nude mice were given micellar paclitaxel at a dose of 25 mg/kg i.v. or 100 mg/kg i.p. in another study, BDF-1 mice were given either micellar paclitaxel or Cremophor paclitaxel at a dose of 20 mg/kg i.v. The mice were sacrificed after a given time and the organs were harvested. Paclitaxel in the organs was extracted with acetonitrile and analyzed using HPLC. Tumor growth inhibitions of 98.5 and 98.7% were obtained from i.v. administered micellar paclitaxel and Cremophor paclitaxel at their MTDs, respectively. Micellar paclitaxel was more efficacious i.p. (98.7% tumor growth inhibition) than Cremophor paclitaxel i.p. (83.0% tumor growth inhibition) at their MTDs. The highest concentrations of paclitaxel were found in the liver after administration of paclitaxel formulations. Paclitaxel was also found in spleen, kidney, lung and blood, in order of decreasing concentration. The preliminary results indicate that polymeric micellar paclitaxel could be a clinically useful chemotherapeutic formulation.

The relatively recent introduction of a new class of chemotherapeutic agents--the taxoids--has raised hope of improved survival for patients with advanced or metastatic cancer. Following encouraging preclinical results of taxoid combinations, this phase I, nonrandomized trial was designed to evaluate a 1-hour intravenous infusion of docetaxel (Taxotere) on day 1 combined with fluorouracil (5-FU) as a daily intravenous bolus for 5 consecutive days. To date, 27 patients with advanced solid neoplasms have received 86 courses of docetaxel/5-FU at the following dose levels: 25/100, 35/150, 50/200, 60/200, and 60/300 mg/m2. Preliminary results showed no unexpected toxicities, and the principal toxicity was neutropenia of short duration. A treatment regimen of 60 mg/m2 docetaxel on day 1 and 300 mg/m2 of 5-FU given for 5 days, with a single course length of 28 days, is projected as the maximum tolerated dose.

Purpose: Patients with AIDS-related lymphoma usually have extensive lymphomatous disease, with relatively frequent involvement of the CNS. Approximately half may achieve complete remission after chemotherapy. Mitoguazone, an inhibitor of polyamine biosynthesis, has demonstrated efficacy in patients with de novo recurrent lymphoma. The drug is relatively nonmyelotoxic and may cross the blood-brain barrier. The current study was designed to assess the safety and potential efficacy of mitoguazone in patients with relapsed or refractory AIDS-lymphoma., Patients and Methods: Thirty-five patients were accrued, all of whom had failed one (51%) or multiple (two to six) prior regimens. Mitoguazone (600 mg/m2) was given intravenously on days 1 and 8, and then every 2 weeks, until best response, progression, or toxicity., Results: The median age was 39 years. High-grade lymphoma was diagnosed in 29 patients (83%). Extranodal disease was present in 30 patients (86%), with multiple extranodal sites (two to seven) in 18 (51%). The median CD4 cell count at study entry was 66/dL (range, zero to 549). Twenty-six patients were assessable for response. The objective response rate was 23% (95% confidence interval [CI], 6.9 to 39.3), with complete remission in three patients (11.5%), and partial remission (PR) in three patients (11.5%). Six patients experienced stable disease. Median survival from study entry was 2.6 months for the group as a whole; 21.5 months (range, 3.8 to 29.1) in complete responders, 5.6 months (range, 3.8 to 34.8) in partial responders. The most common toxicities occurred solely during drug infusion and included vasodilation (63%), paresthesia (86%), and somnolence (17%). Fourteen patients (40%) experienced nausea and 16 (46%) vomiting (grade 3 in one). Ten patients (29%) developed stomatitis, including grade 3 in two and grade 4 in one. Seven patients (20%) developed neutropenia, with grade 4 in one. Thrombocytopenia occurred in nine patients (26%). While on study, three patients developed sepsis, four had pneumonia, and two developed opportunistic infections., Conclusion: Mitoguazone is an effective agent in patients with multiply relapsed or refractory AIDS-related lymphoma, with acceptable toxicity. Further study in patients with newly diagnosed disease is warranted.

The pyrimidine (uracil) analogue 3-oxauracil (OU) previously had been shown to completely inhibit the growth of E. coli B and decrease by 96% the replication of herpes simplex virus type 2 when present in the culture fluid at a concentration of 10(2) microM. Limited in vivo studies in mice demonstrated antiviral effects without significant toxicity when given i.p. daily for two weeks at a concentration of 3.23 mg/kg. However, the antineoplastic properties of OU were unknown. We assessed the ability of OU to inhibit the proliferation of various human tumor cell lines (3 pancreatic, 1 colon, 1 neuroendocrine, and 1 lung) in an in vitro radiometric (Bactec) system. In the pancreatic lines (RWP-2, MiaPaCa-2, and PANC-1), the colon line (HT-29), the neuroendocrine line (COLO 320DM), and the lung cancer cell line (SK-MES-1), OU at a concentration of 10(3) microM, produced a dramatic decrease in percent cell survival. When compared with cytotoxic drugs of choice for these tumor cells (gemcitabine, 5-fluorouracil, and adriamycin, respectively) a significantly higher concentration of OU was required usually to achieve comparable results with two exceptions. These were the HT-29 and the COLO 320DM cell lines. These results indicate OU has significant (p < 0.05) cytotoxic activity against pancreatic, colon, neuroendocrine, and nonsmall cell lung cancer lines, when compared to untreated control cultures. Additional in vivo testing of this potential antineoplastic agent is warranted.

Purpose: To evaluate in vitro cytotoxicity, in vivo antitumour activity and biodistribution of a novel polymeric (poly(DL-lactide)-block-methoxy polyethylene glycol) micellar paclitaxel., Methods: Hs578T breast, SKMES non-small-cell lung, and HT-29 colon human tumour cells were exposed, either for 1 h or continuously, to conventionally formulated paclitaxel (Cremophor paclitaxel) or polymeric micellar paclitaxel. After a period of incubation, cytotoxicity was measured using a radiometric system. In the in vivo antitumour study, B6D2F1 mice, bearing P388 leukaemia tumour intraperitoneally (i.p.), were treated with polymeric micellar paclitaxel or Cremophor paclitaxel by i.p. injection. The number of deaths and body weights were recorded. In the biodistribution study, CD-1 mice were given micellar paclitaxel i.p. at a dose of 100 mg/kg. The mice were sacrificed after a given time and the organs were harvested. Paclitaxel in the organs was extracted by acetonitrile and analysed using HPLC., Results: The polymeric micellar paclitaxel showed similar in vitro cytotoxicity to Cremophor paclitaxel against the tumour cell lines. The polymeric micellar formulation of paclitaxel produced a fivefold increase in the maximum tolerated dose (MTD) as compared with Cremophor paclitaxel when administered i.p. In addition, micellar paclitaxel was more efficacious in vivo when tested in the murine P388 leukaemia model of malignancy than Cremophor paclitaxel when both were administered i.p. at their MTDs. Micellar paclitaxel-treated animals had an increased survival time and, importantly, long-term survivors (20% of those tested) were obtained only in the polymeric paclitaxel formulation group. Biodistribution studies indicated that a significant amount of paclitaxel could be detected in blood, liver, kidney, spleen, lung and heart of mice after i.p. dosing of the polymeric micellar paclitaxel formulation., Conclusion: These preliminary results indicate that polymeric micellar paclitaxel could be a clinically useful chemotherapeutic formulation.

CPT-11 is a new agent with a unique mechanism of action, namely the inhibition of topoisomerase I. An examination of data from the laboratory reveals several leads which should be pursued in the clinic. A dose-response effect for CPT-11 activity has been noted in the human tumour cloning assay. CPT-11 has activity against breast and mesothelioma colony-forming units in a human tumour cloning assay, and has in vivo activity against a number of paediatric malignancies. Promising combinations in preclinical in vivo models include CPT-11/mitomycin C and CPT-11/cytosine arabinoside. There is incomplete cross-resistance among topoisomerase I inhibitors, suggesting that combinations of topoisomerase I inhibitors should be investigated. Several natural products have been identified which have potential to decrease CPT-11-induced diarrhoea. The level of carboxylesterase in a patient's tumour appears to be related to the in vitro activity of CPT-11, suggesting that measurement of carboxylesterase in a patient's tumour could be used to identify patients who are most likely to respond to treatment with CPT-11. These preclinical findings suggest substantial further clinical potential for CPT-11 in terms of decreased CPT-11-induced diarrhoea as well as increased antitumour activity, which should be explored in phase I and II studies.

A better understanding of the biology and biochemistry of the cancer cell has led to the development of various promising new antineoplastic compounds that are now undergoing phase I, II, and III clinical testing. These drugs include topoisomerase I inhibitors, such as camptothecin and its analogs 9-aminocamptothecin, irinotecan, and topotecan; and the paclitaxel analog docetaxel. The authors discussed these new agents last month. In Part 2 of their article, they describe gemcitabine, an antimetabolite structurally related to cytarabine; fluorouracil prodrugs and other thymidylate synthase (TS) inhibitors, and new approaches to anticancer therapy, such as angiogenesis inhibitors, differentiating agents, signal transduction inhibitors, and gene therapy.

The BRCA1 gene product was identified as a 220-kilodalton nuclear phosphoprotein in normal cells, including breast ductal epithelial cells, and in 18 of 20 tumor cell lines derived from tissues other than breast and ovary. In 16 of 17 breast and ovarian cancer lines and 17 of 17 samples of cells obtained from malignant effusions, however, BRCA1 localized mainly in cytoplasm. Absence of BRCA1 or aberrant subcellular location was also observed to a variable extent in histological sections of many breast cancer biopsies. These findings suggest that BRCA1 abnormalities may be involved in the pathogenesis of many breast cancers, sporadic as well as familial.

The primary aim of this report was to examine the significance of increased DNA sequence copy number (gene amplification) in human prostate cancers. Three methodologies (chromosome microdissection, comparative genomic hybridization, and fluorescence in situ hybridization) were combined to (a) identify a common region of gene amplification in human prostate cells and (b) evaluate in patient samples the prevalence of this genetic change in both primary and recurrent prostate samples. The results of chromosome microdissection revealed a common amplified band region (8q24.1-24. 2) in two prostate cases with cytological evidence of gene amplification (double minutes). Fluorescence in situ hybridization using the 8q microdissection probe was performed on fresh tumor touch preparations from 44 randomly selected prostatectomy specimens. Amplification of DNA sequences from 8q24 was observed in 4 (9%) of 44 cases. Four of the 44 patients in this series presented with a positive lymph node at initial diagnosis and 3 of these 4 patients showed 8q amplification. Because of this finding, comparative genomic hybridization and fluorescence in situ hybridization were performed on tumor cells from nine prostate cancer patients with recurrent disease. In eight of nine cases a gain of DNA sequences encompassing 8q24 was observed. Taken together with other evidence implicating 8q gain in prostate cancer progression, these results suggest that the analysis of this genetic change may have diagnostic utility as a marker of prostate cancer progression.

Taxol is a unique mitotic inhibitor that has entered phase II investigation. Phase I studies demonstrated hypersensitivity reactions that were related to the cremophor vehicle and to the rate of drug infusion. As a result, the time span of intravenous (IV) infusion of taxol was routinely prolonged to 6 hours or beyond, and premedication with diphenhydramine, dexamethasone, and cimetidine was initiated. Early studies showed antitumor activity, especially against malignant melanoma and ovarian carcinoma. This phase I trial was performed giving taxol, as a 6-hour IV infusion every 21 days, without premedication. The purpose was to study the necessity of premedication and its impact on toxicity and pharmacokinetics. Thirty-one patients received 64 assessable courses of taxol. One patient had a hypersensitivity reaction, which was easily controlled using routine measures. Myelosuppression was dose-limiting, but sporadic, with two fatalities due to sepsis. Nonhematologic toxicity was of grade 1 and 2 except for one patient with grade 3 mucositis and two patients with grade 3 neuropathy. The neuropathy consisted of reversible painful paresthesias, requiring discontinuation of drug in two patients. Four partial responses were seen (three in patients with non-small-cell lung cancer, one in a patient with adenocarcinoma of unknown primary). Pharmacokinetic values were consistent with those previously reported. The occurrence of myelosuppression or neurotoxicity appeared to be associated with the area under the concentration x time curve (AUC) of taxol. The recommended phase II starting dose on this schedule is 225 mg/m2. Taxol merits broad investigation at the phase II level.

Taxol, a novel antimitotic, antitumor agent is currently undergoing Phase 1 clinical trials for the treatment of various tumors. An isocratic HPLC method has been developed for the determination of taxol in human plasma and urine. The method was then applied to the clinical pharmacokinetics of taxol following 6-h intravenous (i.v.) infusions at doses of 175 and 225 mg m-2. A mobile phase of methanol-acetate buffer (0.02 M, pH 4.5) (65:35, v/v) was used to elute a C8 column with detection at 227 nm. The sample preparation involved extraction with t-butyl methyl ether followed by further clean-up of the sample by solid-phase extraction. The method was linear from 0.10-10 microM injected, with a chromatographic run time of 6 min. The results obtained from the clinical study indicate that the plasma pharmacokinetics of taxol are best characterized by a two compartment open body model. Additionally, the present study resulted in the detection of a previously unreported peak which may be a metabolite of taxol.

During a 6-month interval, Eastern Cooperative Oncology Group randomized 127 patients who had received prior chemotherapy, and who had advanced measurable, surgically incurable colorectal cancer, to receive piperazinedione (PZD), Yoshi-864, or razoxane (ICRF-159). The observed response (and median survival) rates were: PZD, one of 35 patients (17 weeks); Yoshi-864, one of 34 (19 weeks), and ICRF-159, none of 38 (23 weeks). Among 107 evaluable patients, there were five episodes of life-threatening toxicity with PZD (one death) and four with ICRF-159 (two deaths). In the same protocol, 42 evaluable patients who had not received prior chemotherapy were randomized to be treated with lomustine (CCNU) or one of the three drugs in the "previously treated" trial. One CR (41 weeks) was seen with ICRF-159 and two PRs were seen with CCNU. Life-threatening toxicity occurred in three patients, two who received CCNU (one death) and one who received PZD. No survival advantage was seen. We do not encourage further phase II trials in colorectal cancer with the agents studied.

Thirty evaluable patients with histologically confirmed primary liver cancer (PLC) were treated with neocarzinostatin (NCS). All patients had measurable disease and an Eastern Cooperative Oncology Group (ECOG) performance status of 1, 2, or 3. NCS 2250 units/m2 was given daily for 5 days, repeated at 28-day intervals. Hemopoietic suppression was the major side effect. In 23 of 30 patients (13 with leukopenia and 19 with thrombocytopenia), this toxic effect was documented. Other toxic effects included nausea, vomiting, allergic-type reaction, and elevation of NPN. Partial response, with a median duration of 12.7 weeks (range 4--37 weeks) was observed in seven patients. In nine patients the response was classified as no change, and in 14 patients there was progressive disease. NCS has some therapeutic activity in patients with PLC.