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Cancer Chemotherapy and Pharmacology

, Volume 31, Issue 3, pp 229–239 | Cite as

Evaluation of 9-dimethylaminomethyl-10-hydroxycamptothecin against xenografts derived from adult and childhood solid tumors

  • Peter J. Houghton
  • Pamela J. Cheshire
  • Leann Myers
  • Clinton F. Stewart
  • Timothy W. Synold
  • Janet A. Houghton
Original Articles 9-Dimethylaminomethyl-10-Hydroxycamptothecin, Xenografts, Solid Tumors, Children

Abstract

The topoisomerase I inhibitor 9-dimethylaminomethyl-10-hydroxycamptothecin (topotecan) was evaluated against a panel of xenografts comprising four lines of adult colon adenocarcinoma, three colon tumors derived from adolescents, six childhood rhabdomyosarcomas from previously untreated patients as well as sublines selected in vivo for resistance to vincristine and melphalan, and three lines of childhood osteogenic sarcoma. Efficacy was determined at maximal tolerated dose levels using intermittent i.p. administration [every 4 days for 4 doses (q4d×4)] or daily p.o. or i. p. administration 5 days per week for up to 20 courses. On a q4d×4 schedule, the maximum tolerated dose (MTD) was 12.5 mg/kg per administration, which caused marked weight loss and lethality in ≈5% of the tumor-bearing mice. This schedule caused significant growth inhibition (but no tumor regression) in advanced adult colon adenocarcinomas. The minimal treated/control (T/C) ratios were 0.49, 0.54, and 0.3 for three of the tumor lines and were achieved at 18–21 days after the initiation of treatment. In contrast, rhabdomyosarcomas were considerably more sensitive, with T/C ratios being <0.1 for three lines, whereas topotecan was less active against two other rhabdomyosarcoma xenografts (minimal T/C ratios, 0.17 and 0.14). As inhibitors of topoisomerase I have been demonstrated to have activity in the replication phase of the cell cycle (S-phase-specific), prolonged administration schedules were examined. Mice received topotecan 5 days per week for 3 weeks either by i.p. injection or by oral gavage (p.o.). In selected experiments, p.o. administration was continued for up to 20 weeks. Oral administration for 3 weeks (2 mg/kg per dose) resulted in complete regression of all six lines of rhabdomyosarcoma, with two lines demonstrating no regrowth during the period of observation (≥84 days). Similar results were obtained after i.p. administration, suggesting significant schedule dependency for these tumors. For colon tumors, the daily administration schedule (i.p. or p.o.) demonstrated some advantage over the intermittent schedule, resulting in partial regressions and significant inhibition of the growth of several colon adenocarcinoma lines. In rhabdomyosarcoma Rh 12 and VRC5 colon adenocarcinoma, both of which demonstrated intermediate sensitivity to topotecan, and in osteosarcoma OS33, protracted p.o. administration for 13–20 weeks (1.0–1.5 mg/kg per dose given daily x 5 days) caused complete regression without regrowth in Rh12 and OS33 tumors and partial regression of all VRC5 tumors. No toxicity was observed using this schedule of administration. Topotecan demonstrated significant activity against all three osteosarcoma xenografts examined, with optimal schedules causing complete regression in two lines. Topotecan demonstrated similar activity against KB 3-1 and KB 8-5 multidrug-resistant cells in culture, and the Rh 12/VCR an Rh 18/VCR xenografts selected for vincristine (VCR) resistance in vivo were as sensitive as their parental lines. However, Rh 28/L-PAM, selected for resistance to melphalan, was cross-resistant to topotecan. Plasma pharmacokinetics studies were carried out at the respective MTD for oral (2 mg/kg) or i.p. (1.75 mg/kg) administration. During oral administration the maximal plasma concentration (of the active lactone) was achieved at 0.25 h (Cmax 41.7 ng/ml) and thet1/2α andt1/2β values were 0.55 and 2.8 h, respectively. Administration i.p. resulted in peak plasma levels of 523 ng/ml, witht1/2α andt1/2β elimination rates being 0.29 and 2.5 h, respectively. Although i.p. administration resulted in a 3-fold increase in AUC as compared with oral dosing, similar antitumor activity was observed against most xenograft lines. These results suggest that topotecan may have significant activity against several human cancers and that its efficacy may be schedule-dependent. Topotecan may have a particular role to play in the treatment of childhood solid tumors such as rhabdomyosarcoma and osteosarcoma.

Keywords

Osteosarcoma Maximum Tolerate Dose Topotecan Rhabdomyosarcoma Colon Adenocarcinoma 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

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References

  1. 1.
    Akiyama S-I, Fojo A, Hanover JA, Pastan I, Gottesman MM (1985) Isolation and genetic characterization of human, KB cell lines resistant to multiple drugs. Somatic Cell Mol Genet 11: 117Google Scholar
  2. 2.
    Beijnen JH, Smith BR (1990) High-performance liquid chromatographic analysis of the new antitumor drug SK&F 104864-A (NSC 609 699). J Pharm Biomed Anal 8: 789Google Scholar
  3. 3.
    Bino GD, Lassota P, Darzynkiewicz Z (1991) The S-phase cytotoxicity of comptothecin. Exp Cell Res 193: 27Google Scholar
  4. 4.
    Chan HSL, Thorner PS, Haddad G, Ling V (1990) Immunohistochemical detection of P-glycoprotein: prognostic correlation in soft tissue sarcoma of childhood. J Clin Oncol 8: 689Google Scholar
  5. 5.
    Chan HSL, Thorner PS, Haddad G, Ling V (1991) Outcome of therapy in osteosarcoma correlates with P-glycoprotein expression. Proc Am Assoc Cancer Res 32: 366Google Scholar
  6. 6.
    D'Argenio DZ, Schumitzky A (1990) ADAPT II user's guide. Biomedical Simulations Resource, University of Southern California, Los AngelesGoogle Scholar
  7. 7.
    Dombernowsky P, Nissen NI (1973) Schedule dependency of the antileukemic activity of the podophyllotoxin derivative VP-16-213 (NSC 141 540) in L1210 leukemia. Acta Pathol Microbiol Scand [A] 81: 715Google Scholar
  8. 8.
    Douglass EC, Valentine M, Etcubanas E, Parham DM, Webber BC, Houghton JA, Houghton PJ, Green AA (1987) A specific chromosomal abnormality in rhabdomyosarcoma. Cytogenet Cell Genet 45: 148Google Scholar
  9. 9.
    Fojo AT, Veda K, Slamon DJ, Poplack DG, Gottesman MM, Pastan I (1987) Expression of a multidrug-resistance gene in human tumors and tissues. Proc Natl Acad Sci USA 84: 265Google Scholar
  10. 10.
    Giovanella BC, Stehlin JS, Wall ME, Wani MC, Nicholas AW, Liu LF, Silber R, Pomesil M (1989) DNA topoisomerase I-targeted chemotherapy of human colon cancer xenografts. Science 246: 1046Google Scholar
  11. 11.
    Gottlieb JA, Luce JK (1972) Treatment of malignant melanoma with camptothecin (NSC-100 880). Cancer Chemother Rep 56: 103Google Scholar
  12. 12.
    Gottlieb JA, Guarino AM, Call JB, Oliverio VT, Block JB (1970) Preliminary pharmacologic and clinical evaluation of camptothecin sodium (NSC 100 880). Cancer Chemother Rep 54: 461Google Scholar
  13. 13.
    Hazelton BJ, Houghton JA, Parham DM, Douglass EC, Torrance PM, Holt H, Houghton PJ (1987) Characterization of cell lines derived from xenografts of childhood rhabdomyosarcoma. Cancer Res 47: 4501Google Scholar
  14. 14.
    Horowitz ME, Etcubanas E, Christensen ML, Houghton JA, George SL, Green AA, Houghton PJ (1987) Phase II testing of melphalan in children with newly diagnosed rhabdomyosarcoma: a model for anticancer drug development. J Clin Oncol 6: 308Google Scholar
  15. 15.
    Horton JK, Houghton PJ, Houghton JA (1987) Reciprocal cross-resistance in human rhabdomyosarcomas selected in vivo for primary resistance to vincristine andl-phenylalamine mustard. Cancer Res 47: 6288Google Scholar
  16. 16.
    Horton JK, Houghton JA, Houghton PJ (1991) Expression of multidrug resistance gene (mdrl) in human tumor xenografts sensitive and resistant to natural products: failure to predict chemosensitivity. J Cell Pharmacol 2: 208Google Scholar
  17. 17.
    Houghton JA, Houghton PJ (1980) On the mechanism of cytotoxicity of fluorinated pyrimidines in four human colon adenocarcinoma xenografts maintained in immune-deprived mice. Cancer 45: 1159Google Scholar
  18. 18.
    Houghton JA, Houghton PJ (1987) The suitability and use of human tumor xenografts. In: Kallman RF (ed) Rodent tumor models in experimental cancer therapy. Pergamon, New York, p 199Google Scholar
  19. 19.
    Houghton JA, Taylor DM (1978) Maintenance of biological and biochemical characteristics of human colorectal tumours during serial passage in immune-deprived mice. Br J Cancer 37: 199Google Scholar
  20. 20.
    Houghton JA, Taylor DM (1978) Growth characteristics of human colorectal tumours during serial passage in immune-deprived mice. Br J Cancer 37: 213Google Scholar
  21. 21.
    Houghton JA, Houghton PJ, Webber BL (1982) Growth and characterization of childhood rhabdomyosarcomas as xenografts. J Natl Cancer Inst 68: 437Google Scholar
  22. 22.
    Houghton JA, Cook RL, Lutz PJ (1984) Childhood rhabdomyosarcoma xenografts: response to DNA interacting agents and agents used in current clinical therapy. Eur J Cancer Clin Oncol 20: 955Google Scholar
  23. 23.
    Houghton JA, Cook RL, Lutz PJ, Houghton PJ (1985) Melphalan: a potential new agent in the treatment of childhood rhabdomyosarcoma. Cancer Treat Rep 69: 9Google Scholar
  24. 24.
    Houghton JA, Houghton PJ, Hazelton BJ, Douglass EC (1985) In situ selection of a human rhabdomyosarcoma resistant to vincristine with altered β-tubulins. Cancer Res 45: 2706Google Scholar
  25. 25.
    Houghton PJ, Houghton JA, Myers L, Cheshire PJ, Howbert JJ, Grindey GB (1989) Evaluation ofN-(5-indanylsulfonyl)-N′-(4-chlorophenyl) urea against xenografts of pediatric rhabdomyosarcoma. Cancer Chemother Pharmacol 25: 84Google Scholar
  26. 26.
    Houghton PJ, Shapiro DN, Houghton JA (1991) Rhabdomyosarcoma, from the laboratory to the clinic. Pediatr Clin North Am 38: 349Google Scholar
  27. 27.
    Johnson DH, Greco FA, Strupp J, Handek R, Hainsworth JD (1990) Prolonged administration of oral etoposide in patients with relapsed or refractory small-cell lung cancer. A phase II trial. J Clin Oncol 8: 1613Google Scholar
  28. 28.
    Kingsbury WD, Boehm JC, Jakas DR, Holden KG, Hecht SM, Gallagher G, Caranfa MJ, McCabe FL, Faucette LF, Johnson RK, Hertzberg RP (1990) Synthesis of water-soluble (aminoalkyl) camptothecin analogues: inhibition of topoisomerase I and antitumor activity. J Med Chem 34: 98Google Scholar
  29. 29.
    Kuhn J, Burris S, Wall J et al. (1990) Pharmacokinetics of the topoisomerase I inhibitor. SK&F 104 864. Proc am Soc Clin Oncol 9: 70Google Scholar
  30. 30.
    Meyer WH, Houghton JA, Houghton PJ, Webber BL, Look AT (1990) Development and characterization of pediatric osteosarcoma xenografts. Cancer Res 50: 2781Google Scholar
  31. 31.
    Meyer WH, Loftin SK, Houghton JA, Houghton PJ (1990) Accumulation, intracellular metabolism, and antitumor activity of high-and low-dose methotrexate in human osteosarcoma xenografts. Cancer Commun 2: 219Google Scholar
  32. 32.
    Moertel CG, Schutt AJ, Reitemeier RJ, Hahn RG (1972) Phase II study of camptothecin (NSC-100 880) in the treatment of advanced gastrointestinal cancer. Cancer Chemother Rep 56: 95Google Scholar
  33. 33.
    Rowinsky E, Grochow C, Hendricks C et al. (1991) Phase I and pharmacokinetic study of topotecan (SK&F 104 864). Proc Am Soc Clin Oncol 10: 93Google Scholar
  34. 34.
    Sirott MN, Saltz L, Young C, et al. (1991) Phase I and clinical pharmacologic study of intravenous topotecan (T). Proc Am Soc Clin Oncol 10: 104Google Scholar
  35. 35.
    Wall J, Burris H, Rodriguez G et al. (1991) Phase I trial of topotecan (SK&F 104 864) in patients with refractory solid tumors. Proc Am Soc Clin Oncol 10: 98Google Scholar
  36. 36.
    Wang JC (1985) DNA topoisomerases. Annu Rev Biochem 54: 665Google Scholar

Copyright information

© Springer-Verlag 1992

Authors and Affiliations

  • Peter J. Houghton
    • 1
  • Pamela J. Cheshire
    • 1
  • Leann Myers
    • 1
  • Clinton F. Stewart
    • 2
  • Timothy W. Synold
    • 2
  • Janet A. Houghton
    • 1
  1. 1.Laboratories for Experimental Therapeutics, Department of Biochemical and Clinical PharmacologySt Jude Children's Research HospitalMemphisUSA
  2. 2.Laboratories for Experimental Therapeutics, Department of PharmaceuticsSt Jude Children's Research HospitalMemphisUSA

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