Extreme lymphoplasmacytosis and hepatic failure associated with sulfasalazine hypersensitivity reaction and a concurrent EBV infection--case report and review of the literature.

We present an unusual case of a patient with extreme lymphoplasmacytosis and hepatic failure in association with a reaction to sulfasalazine and a concurrent Epstein-Barr virus (EBV) infection. Sulfa drugs can cause a wide range of allergic and hypersensitivity reactions and occasionally can lead to a fulminant illness. In the case under discussion the patient had hepatotoxicity, skin rash, fever, and peripheral blood atypical lymphocytosis. Initial impressions suggested the possibility of a malignant lymphoproliferative disorder. Flow cytometry of peripheral blood and a bone marrow biopsy provided clear evidence for a reactive, polyclonal process as opposed to a malignant disorder. Cessation of the offending drug and administration of steroids led to dramatic improvement. This case illustrates that drug hypersensitivity reactions can be manifested by an extreme lymphocytoid leukemoid reaction.

Attitudes and practices among pediatric oncologists regarding end-of-life care: results of the 1998 American Society of Clinical Oncology survey.

PURPOSE: In 1998, the American Society of Clinical Oncology (ASCO) surveyed its membership to assess the attitudes, practices, and challenges associated with end-of-life care of patients with cancer. In this report, we summarize the responses of pediatric oncologists and the implications for care of children dying from cancer. METHODS: The survey consisted of 118 questions, covering eight categories. All ASCO members in the United States, Canada, and the United Kingdom were mailed a survey, which was completed by 228 pediatric oncologists. Predictors of particular attitudes and practices were identified using stepwise logistic regression analysis. Potential predictors were age, sex, religious affiliation, importance of religious beliefs, recent death of a relative, specialty, type of practice (rural or urban, academic or nonacademic), amount of time spent in patient care, number of new patients in the past 6 months, and number of patients who died in the past year. RESULTS: Pediatric oncologists reported a lack of formal courses in pediatric palliative care, a strikingly high reliance on trial and error in learning to care for dying children, and a need for strong role models in this area. The lack of an accessible palliative care team or pain service was often identified as a barrier to good care. Communication difficulties exist between parents and oncologists, especially regarding the shift to end-of-life care and adequate pain control. CONCLUSION: Pediatric oncologists are working to integrate symptom control, psychosocial support, and palliative care into the routine care of the seriously ill child, although barriers exist that make such comprehensive care a challenge.

SMARCAD1, a novel human helicase family-defining member associated with genetic instability: cloning, expression, and mapping to 4q22-q23, a band rich in breakpoints and deletion mutants involved in several human diseases.

Members of the DEAD/H box-containing helicase superfamily include proteins essential to genome replication, repair, and expression. We report here the cloning and initial characterization of a novel human member of this protein family, designated hHel1 (human helicase 1), now designated SMARCAD1 by HUGO. This DEAD/H box-containing molecule has seven highly conserved sequence regions that allow us to place it in the SNF2 family of the helicase superfamily. Uniquely, though, hHel1 contains two DEAD/H box motifs, a property not reported to be shared by any other SNF2 family members. This defines a new subfamily consisting of hHel1 and its homologues. In addition to these DEAD/H box/ATP-binding motifs, hHel1 has a putative nuclear localization signal and several regions that may mediate protein-protein interactions. Expression analysis indicates that hHel1 transcripts are ubiquitous, with particularly high levels in endocrine tissue. We have mapped the gene for hHel1 to human chromosome 4q22-q23; this region is rich in breakpoints and deletion mutants of genes involved in several human diseases, notably soft tissue leiomyosarcoma, hepatocellular carcinoma, and hematologic malignancies. Our observation that human Hel1 gene overexpression is present in an E1A-expressing cell line with increased capacity for gene reactivation events by genomic rearrangement suggests that human Hel1 may play a role in genetic instability development.

Attitudes and practices of U.S. oncologists regarding euthanasia and physician-assisted suicide.

BACKGROUND: The practices of euthanasia and physician-assisted suicide remain controversial. OBJECTIVE: To achieve better understanding of attitudes and practices regarding euthanasia and physician-assisted suicide in the context of end-of-life care. DESIGN: Cohort study. SETTING: United States. PARTICIPANTS: 3299 oncologists who are members of the American Society of Clinical Oncology. MEASUREMENTS: Responses to survey questions on attitudes toward euthanasia and physician-assisted suicide for a terminally ill patient with prostate cancer who has unremitting pain, requests for and performance of euthanasia and physician-assisted suicide, and sociodemographic characteristics. RESULTS: Of U.S. oncologists surveyed, 22.5% supported the use of physician-assisted suicide for a terminally ill patient with unremitting pain and 6.5% supported euthanasia. Oncologists who were reluctant to increase the dose of intravenous morphine for terminally ill patients in excruciating pain (odds ratio [OR], 0.61 [95% CI, 0.48 to 0.77]) and had sufficient time to talk to dying patients about end-of-life care issues (OR, 0.79 [CI, 0.71 to 0.87]) were less likely to support euthanasia or physician-assisted suicide. During their career, 3.7% of surveyed oncologists had performed euthanasia and 10.8% had performed physician-assisted suicide. Oncologists who were reluctant to increase the morphine dose for patients in excruciating pain (OR, 0.58 [CI, 0.43 to 0.79]) and those who believed that they had received adequate training in end-of-life care (OR, 0.86 [CI, 0.79 to 0.95]) were less likely to have performed euthanasia or physician-assisted suicide. Oncologists who reported not being able to obtain all the care that a dying patient needed were more likely to have performed euthanasia (P = 0.001). CONCLUSIONS: Requests for euthanasia and physician-assisted suicide are likely to decrease as training in end-of-life care improves and the ability of physicians to provide this care to their patients is enhanced.

Cloning and characterization of the 5'-flanking sequence for the human DNA topoisomerase II beta gene.

Mammalian cells express two isoforms of type II DNA topoisomerase which are the intracellular targets of many structurally diverse antineoplastic agents. The levels of topoisomerase II isozymes are important determinants for the sensitivity of cells to the cytotoxicity of drugs that target topoisomerase II. To investigate whether the expression of topoisomerase II isoforms is coordinated and the mechanisms governing their expression in the context of drug resistance, the 5'-flanking sequence for the gene of human topoisomerase IIbeta isoform was cloned and characterized. The 5'-flanking region has a very high GC content and contains no canonical TATA box element. Two separate transcriptional start sites are located to an adenine and a guanine, 193 and 89 nucleotides, respectively, upstream from the ATG translation initiation codon. Except for a small region immediately upstream of the translation initiation codon, there is no obvious sequence homology between the 5'-flanking sequences of human topoisomerase IIbeta gene and the previously described alpha gene. Transient expression assays with different 5'- and 3'-deletions of the 5'-flanking region of the topoisomerase IIbeta gene have delineated regions important for transcriptional regulation of the gene. Interestingly, sequences within the first intron also contribute to the promoter activity. Gel mobility shift studies demonstrate that protein factors from the nuclear extracts can bind specifically to the downstream elements and may participate in transcriptional regulation.

Passage to nonselective media transiently alters growth of mycophenolic acid-resistant mammalian cells expressing the escherichia coli xanthine-guanine phosphoribosyltransferase gene: implications for sequential selection strategies.

The Escherichia coli xanthine-guanine phosphoribosyltransferase gene (Ecogpt) rescues mammalian cells from inhibition of purine nucleotide biosynthesis by mycophenolic acid (MPA). We used Ecogpt and other selectable markers to obtain subclones of NIH 3T3 derivatives (EN/NIH) stably expressing transfected genes of interest. In their respective selective mediums, growth of MPA-resistant (MPA(R)) isolates was indistinguishable from that of aminoglycoside-resistant counterparts expressing selectable marker genes conferring resistance to protein synthesis inhibitors hygromycin B, puromycin, and G418. Growth of aminoglycoside-resistant isolates remained unaltered on passage to nonselective media. In contrast, MPA(R) cells transferred from MPA complete media to nonselective media displayed morphologic changes with static growth. These findings resolved completely by third passage in nonselective media and were independent of the gene of interest cis-linked to the selectable marker. Sequential selection strategies involving cell culture conditions resulting in these altered growth characteristics significantly impaired detection (by selection in G418) of genomic events associated with reactivation of enhancerless, transcriptionally silent neointegrants present in MPA(R) EN/NIH isolates. We explored the cause of these cell culture findings and defined transfection and sequential selection strategies for MPA(R) derivatives that successfully circumvented these effects.

DNA topoisomerase II alpha expression is associated with alkylating agent resistance.

Increased expression of DNA topoisomerase II alpha has been associated with resistance to certain DNA-damaging alkylating agents, but no causal relationship or mechanism has been established. To investigate this observation, we developed a model of topoisomerase II overexpression by transfecting a full-length Chinese hamster ovary topoisomerase II alpha into EMT6 mouse mammary carcinoma. Topoisomerase II alpha-transfected cell lines demonstrated continued topoisomerase II alpha mRNA and protein expression, which were undetectable in vector-only lines, in stationary phase (G0-G1). The topoisomerase II transfectants were approximately 5-10-fold resistant to the alkylating agents cisplatin and mechlorethamine. Upon release from G0-G1, the topoisomerase II transfectants demonstrated more rapid thymidine incorporation and shorter cell-doubling times than control cells. Purified topoisomerase II and nuclear extracts with topoisomerase II-decatenating activity bound to cisplatin-treated DNA with significantly greater affinity than to untreated DNA in a cisplatin concentration-dependent manner. These observations suggest that expression of topoisomerase II alpha may have a role in cellular resistance to antineoplastic alkylating agents. The mechanism for this may involve increased binding of topoisomerase II alpha to alkylating agent-damaged DNA.

Molecular cloning and characterization of the promoter for the Chinese hamster DNA topoisomerase II alpha gene.

To investigate the mechanisms governing the expression of DNA topoisomerase II alpha, the Chinese hamster topoisomerase II alpha gene has been cloned and the promoter region analyzed. There are several transcriptional start sites clustered in a region of 30 base pairs, with the major one being 102 nucleotides upstream from the ATG translation initiation site. Sequencing data reveal one GC box and a total of five inverted CCAAT elements (ICEs) within a region of 530 base pairs upstream from the major transcription start site. Sequence comparison between the human and Chinese hamster topoisomerase II alpha gene promoter regions shows a high degree of homology centered at the ICEs and GC box. In vitro DNase I footprinting results indicate protection by binding proteins at and around each ICE on both DNA strands. However, no obvious protection was observed for the GC box. Competition gel mobility shift assays with oligonucleotides containing either the wild-type or mutated ICE sequences suggest that identical or similar proteins specifically bind at each ICE, although with different affinities for individual ICE sequences. Chloramphenicol acetyltransferase assays employing nested 5'-deletions of the 5'-flanking sequence of the gene demonstrate that the sequence between -186 and +102, which contains three proximal ICEs, is sufficient for near wild-type level of promoter activity. When these three ICEs were gradually replaced with sequences which do not interact with the binding proteins, reducing promoter activity of the resulted constructs was observed. In conjunction with results from footprinting and gel mobility shift studies, the transient gene expression finding suggests that the ICEs are functionally important for the transcriptional regulation of the topoisomerase II alpha gene.

Phase I trial of an interleukin-2 fusion toxin (DAB486IL-2) in hematologic malignancies: complete response in a patient with Hodgkin's disease refractory to chemotherapy.

BACKGROUND: DAB486IL-2 is a recombinant fusion toxin in which the native diphtheria toxin-receptor binding-domain has been replaced with human interleukin-2 (IL-2). This molecule is specifically cytotoxic in vitro within 30 minutes for cells that express the high-affinity IL-2 receptor (IL-2R). METHODS: This was a Phase I/II study of DAB486IL-2 as a brief infusion in 15 patients with refractory lymphoid malignancies. Five patients per cohort received DAB486IL-2 as a 30-60 minute intravenous infusion at dose levels of 0.075, 0.115, and 0.2 mg/kg daily for 5 days. RESULTS: The maximal tolerated dose (MTD) of DAB486IL-2 was determined to be 0.2 mg/kg daily on the basis of hypersensitivity-like symptoms and reversible hepatic transaminase elevations. Other adverse effects included mild creatinine elevations, proteinuria, and hypoalbuminemia. The presence of antibodies to diphtheria toxin or DAB486IL-2 was correlated with hypersensitivity-like effects but did not prevent an antitumor effect. One complete response was observed in a patient with Hodgkin's disease in relapse with bilateral pulmonary nodules after autologous bone marrow transplantation. He remains free of disease more than 2 years after completion of therapy. CONCLUSIONS: The dramatic antitumor response seen in one patient and the relative tolerability of DAB486IL-2 indicates the potential utility of this targeted agent in IL-2-expressing hematologic malignancies.

High-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy: analysis by age.

The analysis was undertaken to determine if the time to progression and survival for women with breast cancer treated with high-dose chemotherapy after a conventional-dose induction therapy differs significantly for women younger and older than 40 years of age. All patients treated in phase II or III protocols of high-dose chemotherapy for breast cancer are included in this analysis. Women were treated on one of six protocols: four sequential phase II protocols for metastatic breast cancer involving cyclophosphamide at a dose of 6000 mg/m2, thiotepa at 500 mg/m2, and carboplatin at 800 mg/m2 (CTCb) chemotherapy; one phase II study of CTCb chemotherapy for stage III or inflammatory breast cancer; and a Cancer and Leukemia Group B phase III study of cyclophosphamide, carmustine, and cisplatin for women with more than 10 involved lymph nodes after primary therapy. Eligibility criteria for the patients with metastatic disease included histologically documented breast cancer, at least a partial response to conventional dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m2, and physiologic age of 18-55 years. Patients with inadequate renal, hepatic, pulmonary, and cardiac function or tumor involvement of marrow or central nervous system were excluded. Of 99 registered patients, three (3%) died of toxicity. There were no toxic deaths in protocols for stage II and III disease, and to date none of these patients have relapsed. Thus, there are no differences by age for these studies.(ABSTRACT TRUNCATED AT 250 WORDS)

Conditional expression of wild-type topoisomerase II complements a mutant enzyme in mammalian cells.

Alterations in the amino acid composition, phosphorylation pattern, or intracellular levels of topoisomerase II have been associated with resistance to antineoplastic agents whose effects are mediated through interactions with this enzyme. To develop a model system with which to investigate the determinants of topoisomerase II sensitivity or resistance to antineoplastic agents that target this enzyme, a cDNA encoding the wild-type Drosophila melanogaster topoisomerase II was ligated into a mammalian expression vector containing a glucocorticoid-inducible mouse mammary tumor virus promoter and transfected into an epipodophyllotoxin-resistant Chinese hamster ovary cell line (VPM(r)-5). In two transfectants carrying an intact, full-length Drosophila topoisomerase II cDNA, exposure to the inducing agent, dexamethasone (10 microM), resulted in complementation of the endogenous mutant topoisomerase II and phenotypic reversion to etoposide sensitivity. In the presence of glucocorticoid, etoposide-induced cytotoxicity increased 20-fold, despite the fact that Drosophila topoisomerase II mRNA expression was only 0.1% of that of the endogenous mammalian topoisomerase II. Induced cells demonstrated a marked increase in DNA single strand breaks compared with uninduced resistant cells, thereby providing biochemical evidence supporting increased DNA strand cleavage due to activation of the Drosophila enzyme. These observations demonstrate the ability of a wild-type Drosophila topoisomerase II to complement a mutant mammalian enzyme and suggest that transfectants capable of conditional topoisomerase II expression represent a useful model for studies of the biochemical pharmacology and structure-function relationships of normal and mutant enzymes.

Molecular cloning and identification of a point mutation in the topoisomerase II cDNA from an etoposide-resistant Chinese hamster ovary cell line.

Topoisomerase II (Top II) is the target enzyme for many antineoplastic drugs such as epipodophyllotoxins, anthracyclines, and acridines. Cell lines with alterations in Top II are resistant to drugs that interact with the enzyme. Studies of the Top II from a Chinese hamster ovary line, VpmR-5, that is resistant to VP-16 and VM-26, demonstrated that it is very similar, qualitatively and quantitatively, to its normal counterpart except that DNA cleavage by the VpmR-5 enzyme is not stimulated by VP-16 or VM-26. To understand the basis for the drug-resistant phenotype, the Top II cDNAs were isolated from both Chinese hamster ovary (CHO) and VpmR-5 cells by cDNA cloning with lambda gt22, and the entire cDNAs were sequenced. A mutation of G-->A at nucleotide 1478 was the only alteration observed in the VpmR-5 Top II cDNA compared with the wild-type gene. The mutation in VpmR-5 was confirmed by sequencing DNA fragments amplified from the genomic DNA by the polymerase chain reaction. Southern blot hybridization analysis of genomic DNA demonstrated loss of a Top II allele in VpmR-5 probably occurred during the development of resistance to etoposide. The mutation in VpmR-5 changes amino acid 493 from arginine to glutamine and is located adjacent to a putative ATP binding site of Top II. Mutations in an analogous region have been identified in two human leukemia cell lines by amplification of segments of Top II cDNA with Taq DNA polymerase. Taken together, these observations suggest that mutations in this region of the gyrase B domain of mammalian topoisomerase II may be capable of conferring resistance to antineoplastic agents that interact with this enzyme.

Pulmonary toxicity associated with high dose chemotherapy in the treatment of solid tumors with autologous marrow transplant: an analysis of four chemotherapy regimens.

We retrospectively reviewed the pulmonary toxicity of six high dose chemotherapy protocols using four chemotherapy regimens in the treatment of solid tumors. All protocols used either high dose cyclophosphamide or ifosfamide in combination with one to three additional chemotherapeutic agents. In each protocol autologous bone marrow was reinfused post chemotherapy to shorten the period of severe myelosuppression. Of 178 patients there were 20 cases of fatal or life-threatening pulmonary toxicity including nine cases of pneumonia, nine cases of interstitial pneumonitis and two cases of pulmonary hemorrhage. Pulmonary function tests revealed modest changes in FEV1 and DLCO in the majority of patients, although 24 patients had more dramatic changes in DLCO suggesting interstitial damage. Significant decrements in FEV1 were seen in the BCNU containing regimen. Statistically significant or nearly significant decreases in DLCO were seen after all cyclophosphamide containing regimens. A regimen containing ifosfamide, carboplatin, and etoposide had minimal associated pulmonary toxicity.

A phase II study of high-dose cyclophosphamide, thiotepa, and carboplatin with autologous marrow support in women with measurable advanced breast cancer responding to standard-dose therapy.

PURPOSE: The study was designed to determine the duration of complete response (CR) for patients with unresectable or metastatic breast cancer treated with high-dose cyclophosphamide, thiotepa, and carboplatin (CTCb) while responding to conventional-dose therapy. METHODS: Eligibility criteria included histologically documented metastatic or unresectable breast cancer, at least a partial response (PR) to conventional-dose therapy, no prior pelvic radiotherapy, cumulative doxorubicin of less than 500 mg/m3, and physiologic age between 18 and 55 years. Patients with inadequate renal, hepatic, pulmonary, and/or cardiac function or tumor involvement of marrow or CNS were excluded. Cyclophosphamide 6,000 mg/m2, thiotepa 500 mg/m2, and carboplatin 800 mg/m2 were given by continuous infusion over 4 days. After recovery, sites of prior bulk disease were to be radiated or resected if feasible. RESULTS: Of 29 registered patients, one died of toxicity (3%; hemorrhage). CRs and PRs continued a median of 16 and 5 months after transplant, respectively (26 and 9 months from initiation of chemotherapy for metastatic disease). Of 10 patients transplanted in CR, four have not progressed at 17 to 31 months after transplantation (25 to 43 months after beginning standard-dose therapy). One of four patients with uptake on bone scan as their only sites of residual disease before transplant and one of three who converted from PR to CR with transplant have not progressed at 27 and 29 months, respectively, after transplant. CONCLUSIONS: CTCb is an intensification regimen with a low mortality that delivers a significantly increased dose of agents with known activity at conventional doses in breast cancer. Although the duration of PR is short as expected, CRs appear to be durable.

Oncogenes result in genomic alterations that activate a transcriptionally silent, dominantly selectable reporter gene (neo).

Although oncogenes and tumor suppressor genes have been implicated in carcinogenesis and tumor progression, their relationship to the development of genomic instability has not been elucidated. To examine this role, we transfected oncogenes (polyomavirus middle [Py] and large T [MT and LT]) and adenovirus serotype 5 E1A) into two NIH 3T3-derived cell lines, EN/NIH 2-4 and EN/NIH 2-20. Both cell lines contain two stable integrants of a variant of the retrovirus vector pZipNeoSV(x)1 that has been modified by deletion of the enhancer elements from the long terminal repeats. DNA rearrangements activating the silent neomycin phosphotransferase gene (neo) present in these integrants were identified by selection of cells in the antibiotic G418. Whereas control-transfected EN/NIH cell lines do not yield G418-resistant subclones (GRSs), a fraction of oncogene-transfected EN/NIH 2-4 (8 of 19 Py MT, 5 of 17 Py LT, and 11 of 19 E1A) and 2-20 (7 of 15 Py MT) cell lines gave rise to GRSs at differing frequencies (0.33 x 10(-6) to 46 x 10(-6) for line 2-4 versus 0.11 x 10(-6) to 1.3 x 10(-6) for line 2-20) independent of cell generation time. In contrast, a distinctly smaller fraction of mutant Py MT-transfected EN/NIH cell lines (1 of 10 MT23, 1 of 10 MT1015, and 0 of 10 MT59b) resulted in GRSs. Southern analysis of DNA from selected oncogene-transfected GRSs demonstrated genomic rearrangements of neo-containing cellular DNA that varied in type (amplification and/or novel fragments) and frequency depending on the specific oncogene and EN/NIH cell line used in transfection. Furthermore, only one of the two neo-containing genomic loci present in both EN/NIH cell lines appeared to be involved in these genomic events. In addition to effects related to the genomic locus, these observations support a role for oncogenes in the development of genetic changes associated with tumor progression.

Cisplatin, continuous-infusion 5-fluorouracil, and intermediate-dose methotrexate in the treatment of unresectable non-small cell carcinoma of the lung.

Forty-one patients with unresectable non-small cell carcinoma of the lung (NSCCL) were treated with cisplatin 20 mg/m2/d for 5 days as a daily bolus injection, 5-fluorouracil 800 mg/m2/d by continuous infusion for 5 days, and intermediate-dose methotrexate 200 mg/m2 on days 15 and 22 of a 28-day cycle (PFM). One complete and 23 partial responses were observed, yielding an overall response rate of 60%. There was no significant difference in response rates based on histologic subtype or extent of disease (locally unresectable versus metastatic). Median duration of response was 6 months, and the median survival of all patients was 10 months. Two patients with unresectable disease at presentation became resectable after chemotherapy and remain disease-free at 46+ and 53+ months. Toxicity was modest, with oral mucositis the major adverse effect. Clinically important neutropenia was uncommon. PFM is an active regimen in NSCCL and deserves further study in the "neoadjuvant" setting.

A phase I clinical trial of novobiocin, a modulator of alkylating agent cytotoxicity.

Antineoplastic drug resistance is a major obstacle to improved treatment of most adult cancers in humans. Novobiocin, an antibacterial agent which inhibits the eukaryotic topoisomerase II enzyme, increases the cytotoxicity of several alkylating agents in vitro by the formation of lethal DNA-DNA interstrand cross-links, perhaps by decreasing the repair of drug monoadducts. In murine tumors treated in vivo novobiocin markedly potentiates alkylating agent cytotoxicity without concomitant increases in host toxicity. With this background, a Phase I trial of novobiocin and cyclophosphamide was performed in refractory cancer patients. Novobiocin was given p.o. for 96 h; 750 mg/m2 of i.v. cyclophosphamide was administered at 48 h. Thirty-four patients received 65 courses. The dose-limiting toxicity of novobiocin in this trial was vomiting. The maximum tolerated dose was 6 g/day. Six of 34 patients had Grade III or IV mylosuppression but no dose escalation effect was noted. Three patients developed allergic reactions which resolved completely. No other significant toxicity occurred. While no dose-dependent effect on serum novobiocin levels occurred, 18 of 19 patients treated at greater than or equal to 4 g daily had serum levels greater than or equal to 100 micrograms/ml at steady state, a level which corresponds to levels used in vitro and seen in vivo where the murine novobiocin half-life of 82 min is far less than that seen in humans (6.0 h). Two of 30 evaluable patients had partial responses. Four other patients had stable disease. Four of six had prior disease progression on cyclophosphamide combination therapy. Novobiocin is well tolerated in patients receiving cyclophosphamide and blood levels are in the drug-potentiating range. Phase II trials in cyclophosphamide refractory patients are anticipated.

A phase I trial of continuous-infusion cyclophosphamide in refractory cancer patients.

Cyclophosphamide demonstrates enhanced tumoricidal activity with decreased bone marrow toxicity when given on a divided-dose schedule in certain animal models. A total of 22 patients presenting with refractory metastatic cancer were treated in a phase I trial of continuous infusion of cyclophosphamide over 96 h. Granulocytopenia of less than 500/microliters that lasted for greater than 14 days or thrombocytopenia of less than 25,000/microliters that lasted for greater than 14 days was the target dose-limiting toxicity in the absence of nonhematologic grade 4 toxicity. The maximal tolerated dose was 7 g/m2. Three patients died. Of 21 evaluable patients, 9 responded, including 8/9 who had experienced disease progression during prior oxazaphosphorine-containing combination chemotherapy. Clinically meaningful responses were observed in patients who had demonstrated clinical resistance to an oxazaphosphorine drug given at lower doses.