Phase I and pharmacodynamic study of the topoisomerase I-inhibitor topotecan in patients with refractory acute leukemia.

PURPOSE To determine the feasibility of escalating the hydrophilic topoisomerase I (topo I)-inhibitor topotecan (TPT) above myelosuppressive doses in adults with refractory or relapsed acute leukemias and to assess pharmacodynamic determinants of TPT action. PATIENTS AND METHODS Seventeen patients received 33 courses of TPT as a 5-day infusion at doses ranging from 0.70 to 2.7 mg/m2/d. Pharmacologic studies were performed to determine the TPT concentrations at steady-state (Css) and to examine parameters in the patients' leukemic blasts ex vivo that may be related to TPT sensitivity, eg, topo I content, p-glycoprotein (Pgp) expression, and the inhibitory effects of relevant TPT concentrations on the growth of blast colonies in clonogenic assays relative to the range of TPT Css values achieved. RESULTS Severe mucositis of the oropharynx and perianal tissues was intolerable at TPT doses greater than 2.1 mg/m2/d, the recommended dose for phase II studies in leukemia. One complete response (CR) in a patient with chronic myelogenous leukemia in blast crisis (CML-B) and one partial response (PR) in a patient with acute myelogenous leukemia (AML) were noted. Significant reductions in circulating blast-cell numbers occurred in all courses, and complete leukemia clearance from the peripheral blood, albeit transient, was noted in 11 courses. TPT Css values ranged from 4.8 to 72.5 nmol/L. Colony-forming assays showed that the TPT LD90 (dose that inhibits the growth of leukemia blast colonies by 90%) values for blasts varied from 6 to 22 nmol/L, a range that overlapped with TPT Css values. In view of these variations in TPT sensitivity, several aspects of topo I-mediated drug action were also studied. In 10 of 11 samples, the multi-drug resistance (Mdr) modulator quinidine altered nuclear daunorubicin (DNR) accumulation and whole-cell TPT accumulation by less than 15%, which suggests that Pgp-mediated effects on drug efflux are insufficient to explain the fourfold range of TPT sensitivities in the colony-forming assays. Immunohistochemistry showed that topo I was expressed in all of the blasts from individual patients without detectable cell-to-cell heterogeneity in each marrow. Western blots indicated that topo I content varied over a 10-fold range. Although the sample size was small, topo I content appeared to be higher in acute lymphoblastic leukemia (ALL), intermediate in AML, and lower in CML-B. Topo I content did not appear to be related to the proliferative status of the blasts. CONCLUSION These results indicate that substantial dose escalation of TPT above myelosuppressive doses reached in solid-tumor patients is feasible in patients with refractory leukemia, that biologically relevant TPT Css values are achievable, and that further developmental trials are warranted.

[1]  M. Potměšil,et al.  Camptothecins: from bench research to hospital wards. , 1994, Cancer research.

[2]  L. Zwelling,et al.  Topoisomerase II levels and drug sensitivity in adult acute myelogenous leukemia , 1994 .

[3]  J. Mohler,et al.  Elevation of topoisomerase I messenger RNA, protein, and catalytic activity in human tumors: demonstration of tumor-type specificity and implications for cancer chemotherapy. , 1994, Cancer research.

[4]  L. Liu,et al.  Interaction between replication forks and topoisomerase I-DNA cleavable complexes: studies in a cell-free SV40 DNA replication system. , 1993, Cancer research.

[5]  J. Hwang,et al.  Increased synthesis and degradation of DNA topoisomerase I during the initial phase of human T lymphocyte proliferation. , 1993, The Journal of biological chemistry.

[6]  L. Zwelling,et al.  Phase I study of Topotecan, a new topoisomerase I inhibitor, in patients with refractory or relapsed acute leukemia , 1993 .

[7]  E K Rowinsky,et al.  The current status of camptothecin analogues as antitumor agents. , 1993, Journal of the National Cancer Institute.

[8]  P. Hérait,et al.  CPT-11-induced cholinergic effects in cancer patients. , 1993, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[9]  Y. Cheng,et al.  Characterization of camptothecin-resistant Chinese hamster lung cells. , 1992, Biochemical pharmacology.

[10]  L. Grochow,et al.  Effect of P-glycoprotein expression on the accumulation and cytotoxicity of topotecan (SK&F 104864), a new camptothecin analogue. , 1992, Cancer research.

[11]  L. Grochow,et al.  Phase I and pharmacologic study of topotecan: a novel topoisomerase I inhibitor. , 1992, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[12]  Y. Pommier,et al.  Sequential administration of camptothecin and etoposide circumvents the antagonistic cytotoxicity of simultaneous drug administration in slowly growing human colon carcinoma HT-29 cells. , 1992, European journal of cancer.

[13]  Y. Miura,et al.  Effects of CPT‐11 in combination with other anti‐cancer agents in culture , 1992, International journal of cancer.

[14]  M. Fukuoka,et al.  Phase I study of weekly intravenous infusions of CPT-11, a new derivative of camptothecin, in the treatment of advanced non-small-cell lung cancer. , 1991, Journal of the National Cancer Institute.

[15]  L. Liu,et al.  Topoisomerase II levels during granulocytic maturation in vitro and in vivo. , 1991, Cancer research.

[16]  S. Kaufmann,et al.  Antagonism between camptothecin and topoisomerase II-directed chemotherapeutic agents in a human leukemia cell line. , 1991, Cancer research.

[17]  J. Boehm,et al.  Synthesis of water-soluble (aminoalkyl)camptothecin analogs: inhibition of topoisomerase I and antitumor activity , 1991 .

[18]  C. Bloomfield,et al.  Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. , 1990, Journal of clinical oncology : official journal of the American Society of Clinical Oncology.

[19]  B. Zehnbauer,et al.  In vitro evaluation of combination drug purging for autologous bone marrow transplantation. , 1990, Bone marrow transplantation.

[20]  S. Howell,et al.  Effect of topoisomerase modulators on cisplatin cytotoxicity in human ovarian carcinoma cells. , 1990, European journal of cancer.

[21]  L. Liu,et al.  DNA topoisomerase I--targeted chemotherapy of human colon cancer in xenografts. , 1989, Science.

[22]  K. Kohn,et al.  Structure-activity study of the actions of camptothecin derivatives on mammalian topoisomerase I: evidence for a specific receptor site and a relation to antitumor activity. , 1989, Cancer research.

[23]  R. Sternglanz,et al.  Evidence that DNA topoisomerase I is necessary for the cytotoxic effects of camptothecin. , 1988, Molecular pharmacology.

[24]  L. Liu,et al.  Proliferation-dependent regulation of DNA topoisomerase II in cultured human cells. , 1988, Cancer research.

[25]  L. Liu,et al.  Identification of mammalian DNA topoisomerase I as an intracellular target of the anticancer drug camptothecin. , 1988, Cancer research.

[26]  R. Hertzberg,et al.  Camptothecin induces protein-linked DNA breaks via mammalian DNA topoisomerase I. , 1985, The Journal of biological chemistry.

[27]  M. Muller,et al.  Eukaryotic type I topoisomerase is enriched in the nucleolus and catalytically active on ribosomal DNA. , 1985, The EMBO journal.

[28]  H. Gralnick,et al.  The Morphological Classification of Acute Lymphoblastic Leukaemia: Concordance among Observers and Clinical Correlations , 1981, British journal of haematology.