Local Hyperthermia in Combination with Chemotherapeutic Agents

  • M. Urano
  • J. Kahn
  • H. Majima


It has been demonstrated that the cytotoxic effect of some chemotherapeutic agents is enhanced at elevated temperatures (Johnson and Pavelec, 1973, Hahn, 1978). As early as 1960 a clinical trial of combined hyperthermia and drug perfusions was performed on the patients with head and neck tumors (Woodhall et al, 1960). The combined use of hyperthermia and chemotherapeutic agents has been extensively studied since the early 1970s. Johnson and Pavelec (1973) demonstrated that the effect of an alkylating agent, thio-TEPA, on Chinese hamster fibroblasts was enhanced at elevated temperatures in vitro. The mechanism of this enhancement appeared to be due to an increased rate constant of alkylation at elevated temperatures. Hahn and his colleagues (1975) have demonstrated thermal enhancement of cytotoxicity of various agents and proposed additional mechanisms of thermal enhancement.


Chemotherapeutic Agent Alkylating Agent Local Hyperthermia Increase Rate Constant Murine Fibrosarcoma 
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.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Adwankar MK, Chitnis MP (1986) Modification of tumor cell sensitivity to antineoplastic agents lonidamine and bouvardin (NSC 259968) at elevated temperatures. Neoplasma 33: 217–223PubMedGoogle Scholar
  2. Alberts DS, Peng Y-M, Chen HSG, Moon TE, Cetas TC, Hoeschele JD (1980) Therapeutic synergism of hyperthermia-cisplatinum in a mouse tumor model. Natl Cancer Inst 65: 455–461Google Scholar
  3. Bates DA, MacKillop WJ (1986) Hyperthermia, adriamycin transport, and cytotoxicity in drug-sensitive and -resistant Chinese hamster ovary cells. Cancer Res 46: 5477–5481PubMedGoogle Scholar
  4. Braun J, Hahn GM (1975) Enhanced cell killing by bleomycin and 43°C hyperthermia and the inhibition of recovery from potentially lethal damage. Cancer Res 35: 2921–2927PubMedGoogle Scholar
  5. Bronk BV, Wilkins RJ, Regan JD (1973) Thermal enhancement of DNA damage by an alkylating agent in human cells. Biochem Biophys Res Commun 52: 1064–1070PubMedCrossRefGoogle Scholar
  6. Brouwer J, Fichtinger-Schepman AMS, van de Putten P, Reedijk J (1982) Influence of temperature on platinum binding to DNA, cell killing, and mutation induction in Escherichia coli K-12 cells treated with cisdiamminedichloroplatinum. Cancer Res 42: 2416–2419PubMedGoogle Scholar
  7. Calderwood SK, Dickson JA (1980) Effect of hyperglycemia on blood flow, pH and response to hyperthermia (42°) of the Yoshida sarcoma in the rat. Cancer Res 40: 4728–4733PubMedGoogle Scholar
  8. Chapman IV, Leyko W, Gaozdzinski K, Koter M, Grzelinska E, Bartosz G (1983) Hyperthermia modification of bleomycinDNA interaction detected by electron spine response. Radiat Res 96: 518–522PubMedCrossRefGoogle Scholar
  9. Dahl O, Mella O (1982) Enhanced effect of combined hyperthermia and chemotherapy (bleomycin, BCNU) in a neurogenic rat tumour (BT4A) in vivo. Anticancer Res 2: 359–364PubMedGoogle Scholar
  10. Dahl O, Mella O (1983) Effect of timing and sequence of hyperthermia and cyclophosphamide on a neurogenic rat tumor (BT4A) in vivo. Cancer 52: 983–987PubMedCrossRefGoogle Scholar
  11. Donaldson SS, Gordon LF, Hahn GM (1978) Protective effect of hyperthermia against the cytotoxicity of actinomycin D on Chinese hamster cells. Cancer Treat Rep 62: 1489–1495PubMedGoogle Scholar
  12. Eichholtz-Wirth H, Hietel B (1986) The relationship between cisplatin sensitivity and drug uptake into mammalian cells in vitro. Br J Cancer 54: 239–243PubMedCrossRefGoogle Scholar
  13. Engelhardt R (1987) Hyperthermia and drugs. Recent Results Cancer Res 104: 136–203PubMedCrossRefGoogle Scholar
  14. George KC, Singh BB (1982) Synergism of chlorpromazine and hyperthermia in two mouse solid tumours. Br J Cancer 45: 309–313PubMedCrossRefGoogle Scholar
  15. Groos E, Walker L, Masters JRW (1986) Intravesical chemotherapy. Studies on the relationship beween pH and cytotoxicity. Cancer 58: 1199–1203PubMedCrossRefGoogle Scholar
  16. Gullino PM, Grantham FH, Smith SH, Haggerty AC (1965) Modification of the acidbase status of the internal milieu of tumors. J Nati Cancer Inst 34: 857–869Google Scholar
  17. Hahn GM (1975) Thermochemotherapy: Interactions between hyperthermia and chemotherapeutic agents. Proceedings of International Symposium on Cancer Therapy by Hyperthermia and Radiation, 2830 April 1975. Washington, DC.Google Scholar
  18. Hahn GM (1978) Interactions of drugs and hyperthermia in vitro and in vivo. In: Streffer E, van Beuningen D, Dietzel F, Rötinger E, Robinson JE, Scherer E, Seeber S, Trott K-R (eds) Cancer Therapy by Hyperthermia and Radiation. Urban & Schwarzenberg, Baltimore-Munich, pp 72–79Google Scholar
  19. Hahn GM, Braun J, Har-Kedar I (1975) Thermochemotherapy: Synergism between hyperthermia (42–43°) and adriamycin (or bleomycin) in mammalian cell inactivation. Proc Natl Acad Sci USA 72: 937–940PubMedCrossRefGoogle Scholar
  20. Hahn GM, Li GG, Shiu E (1977) Interaction of amphotericin B and 43° hyperthermia. Cancer Res 37: 761–764PubMedGoogle Scholar
  21. Hahn GM, Shiu EC (1983) Effect of pH and elevated temperatures on the cytotoxicity of some chemotherapeutic agents on Chinese hamster cells in vitro. Cancer Res 43: 5789–5791PubMedGoogle Scholar
  22. Henle KS, Dethlefsen LA (1978) Heat fractionation and thermotolerance: A review. Cancer Res 38: 1843–1851PubMedGoogle Scholar
  23. Herman TS, Teicher BA (1988) Sequencing of trimodality therapies: cis-diamminedichloroplatinum ( II)/hyperthermia/radiation by tumor growth delay and human cell survival in the FSaIIC fibrosarcoma. Cancer Res 48: 2693–2697PubMedGoogle Scholar
  24. Herman TS, Teicher BA, Chan V, Collins LS, Abrams MJ (1989) Effect of heat on the cytotoxicity and interaction with DNA of a series of platinum complexes. Int J Radiat Oncol Biol Phys 16: 443–449PubMedCrossRefGoogle Scholar
  25. Herman TS, Teicher BA, Collins LS (1988) Effect of hypoxia and acidosis on the cytotoxicity of four platinum complexes at normal and hyperthermic temperatures. Cancer Res 48: 2342–2347PubMedGoogle Scholar
  26. Honess DJ, Bleehen NM (1982) Sensitivity of normal mouse marrow and RIF-1 tumour to hyperthermia combined with cyclophosphamide or BCNU: A lack of therapeutic gain. Br J Cancer 46: 236–246PubMedCrossRefGoogle Scholar
  27. Honess DJ, Bleehen NM (1985) Thermo-chemotherapy with cis-platinum, CCNU, BCNU, chlorambucil and melphalan on murine marrow and two tumours: Therapeutic gain for melphalan only. Br J Radiol 58: 63–72Google Scholar
  28. Jain RK, Ward-Hartley K (1984) Tumor blood flow-characterization, modifications and role in hyperthermia. IEEE Trans Sonics Ultrasonics 54 /31: 504–526Google Scholar
  29. Johnson HA, Pavelec M (1973) Thermal enhancement of thio-TEPA cytotoxicity. Nati Cancer Inst 50: 903–908Google Scholar
  30. Kohn KW, Erickson LC, Laurent G, Ducore J, Sharkey N, Ewing RA (1981) DNA crosslinking and the origin of sensitivity to chloroethylnitrosourea. In: PresTaylo AW, Baker LH, Crooke ST, Carter SK, Schein PS, Alder NA (eds) Nitrosourea: Current Status and New Developments. Academic Press, New York, pp 69–83Google Scholar
  31. Longo FW, Tomashefsky P, Rivin BD, Tannenbaum M (1983) Interaction of ultrasonic hyperthermia with two alkylating agents in a murine bladder tumor. Cancer Res 43: 3231–3235PubMedGoogle Scholar
  32. Majima H (1988) Thermotolerance and thermochemotherapy. Hyperthermic Oncology 2: 160–162Google Scholar
  33. Majima H, Urano M, Kahn J (1988) Effect of previous treatment with hyperthermia or bleomycin on the subsequent thermobleomycin treatment. Hyperthermic Oncology 1: 68–70Google Scholar
  34. Marmor JB, Kozak D, Hahn GM (1979) Effects of systemically administered bleomycin or adriamycin with local hyperthermia on primary tumor and lung metastases. Cancer Treatment Reports 63: 1279–1290PubMedGoogle Scholar
  35. Meyn RE, Corry PM, Fletcher SE, Demetriades M (1979) Thermal enhancement of DNA strand breakage in mammalian cells treated with bleomycin. Int J Radiat Oncol Biol Phys 5: 1487–1489PubMedGoogle Scholar
  36. Meyn RE, Corry PM, Fletcher SE, Demetriades M (1980) Thermal enhancement of DNA damage in mammalian cells treated with cis-diamminedichloroplatinum (II). Cancer Res 40: 1136–1139PubMedGoogle Scholar
  37. Morgan JE, Bleehen, NM (1981) Response of EMT6 multicellular tumour spheroids to hyperthermia and cytotoxic drugs. Br J Cancer 43: 384–391PubMedCrossRefGoogle Scholar
  38. Murray D, Milas L, Meyn RE (1984) DNA damage produced by combined hyperglycemia and hyperthermia in two mouse fibrosarcoma tumors in vivo. Int J Radiat Oncol Biol Phys 10: 1679–1682PubMedCrossRefGoogle Scholar
  39. Osborne HJ, MacKillop WJ (1987) The effect of exposure to elevated temperatures on membrane permeability to adriamycin in Chinese hamster ovary cells in vitro. Cancer Lett 37: 213–224PubMedCrossRefGoogle Scholar
  40. Pinto AL, Lippard SJ (1985) Binding of the antitumor drug cis-diamminedichloroplatinum (II) (cisplatin) to DNA. Biochem Biophys Acta 780: 167–180PubMedGoogle Scholar
  41. Reed E, Ozols RF, Tarone R, Yuspa SH, Poirier MC (1987) Platinum-DNA adducts in leukocyte DNA correlate with disease response in ovarian cancer patients receiving platinum-based chemotherapy. Proc Natl Acad Sci [USA] 84: 5024–5028CrossRefGoogle Scholar
  42. Rose WC, Veras GH, Laster WR, Schabel FM Jr (1979) Evaluation of whole-body hyperthermia as an adjuvant to chemotherapy in murine tumors. Cancer Treat Rep 63: 1311–1325PubMedGoogle Scholar
  43. Rotin D, Wan P, Grinstein S, Tannock I (1987) Cytotoxicity of compounds that interfere with the regulation of intracellular pH: A potential new class of anticancer drugs. Cancer Res 47: 1497–1504PubMedGoogle Scholar
  44. Smith PJ, Michera J, Bleehen NM (1986) Interaction of bleomycin, hyperthermia and a calmodulin inhibitor (trifluoperazine) in mouse tumour cells: II. DNA damage, repair and chromatin changes. Br J Cancer 53: 105–114PubMedCrossRefGoogle Scholar
  45. Song CW, Kang MS, Rhee JG, Levitt SH (1980) The effect of hyperthermia on vascular function, pH, and cell survival. Radiology 137: 795–803PubMedGoogle Scholar
  46. Teicher BA, Kowal CD, Kennedy KA, Sartorelli AC (1981) Enhancement by hyperthermia of the in vitro cytotoxicity of mitomycin C toward hypoxic tumor cells. Cancer Res 41: 1096–1099PubMedGoogle Scholar
  47. Terasima T, Yasukawa M, Umezawa, H (1970) Breaks and rejoining of DNA in cultured mammalian cells treated with bleomycin. Gann 61: 513–516PubMedGoogle Scholar
  48. Tofilon PJ, Da Silva V, Gutin PH, Deen DF (1985) Effect of hyperthermia on DNA interstrand crosslinkings after treatment with BCNU in 9L rat brain tumor cells. Radiat Res 103: 373–382PubMedCrossRefGoogle Scholar
  49. Urano M (1986) The kinetics of thermotolerance in normal and tumor tissues. A review. Cancer Res 46: 474–482PubMedGoogle Scholar
  50. Urano M (1988) Tumor response to hyperthermia. In: Urano M, Douple E (eds) Hyperthermia and Oncology, vol 1. VSP, Utrecht, Netherlands, pp 161–200Google Scholar
  51. Urano M, Kahn J (1989) The effect of bleomycin administered in combination with hyperthermia on a C3H mouse fibrosarcoma. Int J Hyperthermia 5: 377–382PubMedCrossRefGoogle Scholar
  52. Urano M, Kahn J, Kenton L (1988a) Effect of bleomycin on murine tumor cells at elevated temperatures and two different pH values. Cancer Res 48: 615–619PubMedGoogle Scholar
  53. Urano M, Kahn J, Kenton L (1988b) Thermochemotherapy-induced resistance to cyclophosphamide. Br J Cancer 57: 295–297PubMedCrossRefGoogle Scholar
  54. Urano M, Kahn J, Kenton LA (1990a) The effect of cis-diamminedichloroplatinum (II) treatment at elevated temperatures on murine fibrosarcoma, FSa-II. Int J Hyperthermia 6: 563–570PubMedCrossRefGoogle Scholar
  55. Urano M, Kahn J, Majima H, Gerweck LE (1990b) The cytotoxic effect of cisdiamminedichloroplatinum (II) on cultured Chinese hamster cells at elevated temperatures. Int J Hyperthermia 6: 581–590PubMedCrossRefGoogle Scholar
  56. Urano M, Kim MS (1983) The effect of hyperglycemia on thermochemotherapy of a spontaneous murine fibrosarcoma. Cancer Res 43: 3041–3044PubMedGoogle Scholar
  57. Urano M, Kim MS, Kahn J, Kenton LA, Li ML (1985) Effect of thermochemotherapy (combined cyclophosphamide and hyperthermia) given at various temperatures with or without glucose administration on a murine fibrosarcoma. Cancer Res 45: 4162–4166PubMedGoogle Scholar
  58. Von Arden M, Reitnauer PG (1980) Selective occlusion of cancer tissue capillaries as the central mechanism of the cancer multistep therapy. Jpn J Clin Oncol 10 (1): 31–48Google Scholar
  59. Wallner KE, Banda M, Li GC (1987) Hyper-thermic enhancement of cell killing by mitomycin C in mitomycin C-resistant Chinese hamster ovary cells. Cancer Res 47: 1308–1312PubMedGoogle Scholar
  60. Wallner KE, Li GC (1987) Effect of drug exposure duration and sequencing on hyperthermic potentiation of mitomycin-C and cisplatin. Cancer Res 47: 493–495PubMedGoogle Scholar
  61. Ward KA, Jain RK (1988) Response of tumours to hyperglycaemia: Characterization, significance and role in hyperthermia. Int J Hyperthermia 4: 223–250PubMedCrossRefGoogle Scholar
  62. Weinkan RJ, Deen DF (1982) Quantitative dose-response relations for the cytotoxic activity of chloroethylnitrosourea in cell culture. Cancer Res 42: 1008–1014Google Scholar
  63. Wike-Hooley JL, Haveman J, Reinhold HS (1984) The relevance of tumour pH to the treatment of malignant disease. Radiother Oncol 2: 343–366PubMedCrossRefGoogle Scholar
  64. Woodhall B, Pickbell KL, Georgiade NG, Mahaley MS, Dukes HT (1960) Effect of hyperthermia upon cancer chemotherapy: Application to external cancer of head and face structures. Ann Surg 151: 750–759PubMedCrossRefGoogle Scholar
  65. Yatvin MB, Muhlensiepen, Porschen W, Weinstein JN, Feinendegen LE (1981) Selective delivery of liposome-associated cis-dichlorodiammineplatinum (II) by heat and its influence on tumor drug uptake and growth. Cancer Res 41: 1602–1607PubMedGoogle Scholar

Copyright information

© Springer-Verlag/Wien 1992

Authors and Affiliations

  • M. Urano
    • 1
  • J. Kahn
    • 2
  • H. Majima
    • 1
  1. 1.Department of Radiation MedicineUniversity of Kentucky Medical CenterUSA
  2. 2.Department of Radiation MedicineMassachusetts General HospitalBostonUSA

Personalised recommendations