• M.W. RANA


Cytological screening by the use of the Papanicolaou smear has significantly reduced thenumber of patients with advanced cervical cancers. Early detection, epidemiology, correct diagnosisand treatment of early stages of cervical lesions have also been effective in control and preventionof cervical cancers. But invasive carcinoma of the cervix is still an important aspect of the cervicalcancer problem. The greatest enigma at this time is the etiology, or predisposing factors, i.e., role ofmale and role of herpes and papilloma viruses in the development of these lesions, which classifiesit as a sexually transmissible disease.1"4 This and other psychological and socio-economic factorsmight hinder some patients from seeking early detection and prevention. There are still hundreds ofcases with advanced lesions reported in literature. Beyond stage II, radiation and chemotherapy arethe only treatment and may not be well tolerated by the patient. Serious complications due toradiation therapy occur most frequently in advanced stages of this disease because of high doses ofradiation which are required to accomplish tumor control.5 It is, therefore, important to seek abroader selection of modes of treatment for this cancer, especially in advanced stages.It is now well established that hyperthermia kills cells in a manner as predictable andrepeatable as radiation and chemotherapy agents.6 Unlike ionizing radiation, hyperthermia kills bothhypoxic and well oxygenated cells.7 Furthermore, neoplastic cells tend to be more sensitive to hyperthermia than do normal cells.8 In addition, heat interacts with radiation and chemotherapeuticagents.9"10 The role of prostaglandin, prostaglandin analogues, and prostaglandin inhibitors in thetreatment of cancer is still controversial. Misonidazol (RO-07--582) has been shown to be anelectron affinic hypoxic cell sensitizer.11,13 It minimizes the effect of oxygen as a reason for failurein the radiation of hypoxic tumors.We report here the effect of hyperthermia, radiation and chemotherapeutic agents, usedalone or in combination, on human carcinoma of the cervix transplanted into athymic (nude) mice,which may offer a broader selection for the treatment of this lesion in human patients.


Christopherson, W.M. and Parker, J.E. A study of the relative frequency of carcinoma of the cervix

in the Negro. Cancer 1960; 13:711-713.

Kessler, II. Human cervical cancer as a venereal disease. Cancer Res. 1976; 36: 783- 791.

Meisels, A. and Morin, C. Human papilloma virus and cancer of the uterine cervix. Gynecol oncol.

; 12: 5111-5123.

Gissman, L., Wolnik, L. and Ikenberg, H. Human papilloma virus type 6 and 11 DNA sequence in

genital and laryngeal papillomas and in some cervical cancers. Proc Natl Acad Sci USA 1983; 80:


Xynos, F.R., Benjamin, I., Sapiente, R., Rana, M.W. and Nalesnik, W.J. Adriamycin and

hydroxyurea as radiopotentiators in the treatment of squamos cell carcinoma of cervix implanted

in nude mice. A preliminary report. Gynecol oncol. 1980; 9: 170-176.

Dewey, W.C. and Holahan, E.V. Hyperthermia—basic biology. In: Rosenblum ML, Wilson C.B,

eds. Progress in Experimental Tumor Research, Brain Tumor Therapy. Switzerland: S. Karger

Medical and Scientific Publishers 1984; 28: 198-219.

Dewey, W.C., Thrall, D.E. and Gillette, E.L. Hyperthermia and radiation. A selective thermal effect

on chronically hypoxic tumor cells in vivo. Int J Radiol oncol Biol Phys 1977; 2: 99-103.

Overgaard, K. and Overgaard, J. Investigation on the possibility of a thermic tumor therapy. I.

Shortwave treatment of a transplanted isologous mouse mammary carcinoma. Eur J Cancer

; 8: 65-78.

Hahn, G.M., Li, G.C. and Shiu, E. Interaction of amphotericin B at 43°C hyperthermia. Cancer

Res. 1977;37:761-764.

Hall, E.J. and Roizin-Towle, L. Biological effects of heat. Cancer Res. 1984; 44: 4708S-4713S.

Devenkamp, J. and Stewart, E.A. Sensitization of mouse tumors using fractionated x-irradiation.

Brit. J. Cancer. 1978; 37 (Suppl III): 259-263.

Hill, R.P., Bush, R.S. The effect of misonidazole in combination with radiation dose fractionation.

Brit. J. Cancer 1978; 37 (Suppl III): 255-258.

Sheldon, P.W. and Fowler, J.F. Radiosensitization by misonidazole (RO-07-0582) of fractionated

x-ray in a murine tumor. Brit J. Cancer 1978; 37 (Suppl III): 242-245.

Cavaliere, R., Ciocatto, E.C. and Giovanella, BC. Selective heat sensitivity of cancer cells,

biochemical and clinical study. Cancer 1967; 20: 1351-1381.

Connor, W.C., Gerner, E.W., Miller, R.C. and Boone, M.L.M. Prospect for hyperthermia in

human cancer therapy. II. Implication of biological and physical data for the application of

hyperthermia to man. Radiol. 1977; 123: 497-503.

Miller, R.C., Connor, W.C., Heusinkveld, R.S. and Boone, M.L.M. Prospect for hyperthermia in

human cancer therapy. I. Hyperthermia effect in man and spontaneous animal tumors. Radiol

; 1 23: 489-495.

Marmor, J.B., Hielerio, F.J. and Hahn, G.M. Tumor eradication and cell survival after localized

hyperthermia induced by ultrasound. Cancer Res. 1979; 39: 2166- 2171.

Hall, E.J. Hyperthermia: An overview. Natl Cancer Inst Monogr 61: 15-16, 1982.

Dewey W.C., Holahan E.V. Thermobiology—rationale for and problems with utilizing

hyperthermia in radiotherapy of cancer. Cancer Bull. 1982; 34: 200-208.

Kase, K. and Hahn, G.M. Differential heat response of normal and transformed human cells in

tissue culture. Nature, 1975; 255 : 228-230.

Heine, U., Sverak, L., Kondratick, J. and Bonai, R.A. The behavior of Hela-Sa cells under the

influence of supernormal temperatures. J. Ultrastruct Res. 1971; 34: 375-396.

Westura. A. and Dewey, W.E. Variation in sensitivity to heat shock during the cell cycle of Chinese

hamster cell in vitro. Int J. Radiat Biol. 1971; 19: 467-477.

Palzer, R.J. and Heidelberger, C. Studies on the quantitative biology of hyperthermia killing of

Hela cells. Cancer Res. 1973; 33: 415-421.

Hahn, G.M. Metabolic aspects of the role of hyperthermia in mammalian cell inactivation and

their possible relevance to cancer treatment. Cancer Res. 1974; 34: 3117-3123.

Freman, M.L., Dewey, W.C. and Hopwood, L.E. Effect of pH on hyperthermia cell survival. J.

Natl Cancer Irtst. 1977; 58: 1837-1839.

Fajardo, L.F., Egbert, B., Marmor, J. and Hahn, G.M. Effect of hyperthermia in malignant tumor,

Cancer 1980; 45: 613-623.

Overgaard, J. Influence of extracellular pH on the viability and morphology of tumor cells exposed

to hyperthermia. J. Natl Cancer Inst. 1976; 56:1243-1250.

Bowler, K., Duncan, C.J., Gladwell, R.T. and Davison, T.F. Cellular heat injury. Comp Biochem

Physiol. 1973; 45: 441-450.

Li, G.C. and Hahn, G.M. Thermal tolerance and tolerance of adriamycin induced by ethanol.

Nature 1978; 274: 699-701.

Dewey, W.C. Interaction of heat with radiation and chemotherapy. Cancer Res. 1984;44: 4714S-


Harris, M. Temperature-resistant variants in clonal population of pig kidney cells. Exp Cell Res.

; 46: 301-314.

Field, S.B. and Law, M.P. The response of skin to fractionated heat and x-rays. Brit J. Radiol,

; 51: 221-222.

Gerweck, L.E. and DeLaney, T.F. Persistance of thermotolerance in slowly proliferating plateau

phase cells. Radiat Res. 1984; 97: 365-372.

Li, G.C., Evans, R.C. and Hahn, G.M. Modification and inhibition of repair of potentially lethal

x-ray damage by hyperthermia. Radiat Res. 1976; 67: 491-501.

Corry, P.M., Robinson, M.S. and Getz, B.S. Hyperthermic effects on DNA repair mechanisms.

Radiology, 1977; 123: 475-485.

Dewey, W.C., Sapareto, S.A. and Betten, A. Hyperthermic radiosensitization of synchronous

Chinese hamster cells relationship between lethality and chromosomal aberrations. Radiat Res.

; 76: 48-59.

Jorritsma, J.B.M. and Konings, A.W.T. Inhibition of radiation-induced strand breaks by

hyperthermia and its relationship to cell survival after hyperthermia alone. Int J. Radiat Biol.

; 43: 505-516.

Dewey, W.C., Freeman, M.L., Raaphorst, G.P., Clark, E.P., Wong, R.S.L., High- field D.P., Spiro,

I.J., Tomasovic, S.P., Denman, D.L. and Coss, R.A. Cell biology of hyperthermia and radiation.

In: Meyv RE, Withers HR, eds. Radiation Biology in Cancer Research. New York, Raven Press,

; 589-621.

Overgaard, J. and Nielson, O.S. The importance of thermotolerance for the clinical treatment with

hyperthermia. Radiother oncol. 1983; 1: 167-178.

Hahn, G.M., Braun, J. and Har-Kedar, I. Thermochemotherapy: Synergism between

hyperthermia (42-43 C)and adriamycin (or bleomycin) in mammalian cell inactivation. Proc Natl

Acad Sci USA. 1975; 72: 937-940.

Hahn, G.M. and Strande, D.P. Cytotoxic effects of hyperthermia and adriamycin on Chinese

hamster cells. J Natl Cancer Inst. 1976; 57: 1063-1067.

Hahn, G.M. Hyperthermia and Cancer. New York, Plenum Publishing Corp. 1982; 74-86.

Roizin-Towle, L., Hall, E.J. and Capuano, 1. Interaction of hyperthermia and cytotoxic agents.

Natl Cancer Inst Monogr. 1982; 61: 149-151.

Fowler, J.E., Adams, G.E. and Devenkamp, J. Radiosensitizers of hypoxic cells in solid tumors.

Cancer Treatment Rev. 1976; 3: 227-256.

Wada, J., Suzuki, T. and Iwasaki, M. A new non-steroidal anti-inflammatory agent. 2-substituted

or 6-benzothiozoleacetic acids and their derivations. J Med Chem. 1973; 16: 930-934.

Knight, R.C., Rowley, D.A., Skolimowski, I. and Edwards, D.I. Mechanism of action of

nitromidazole antimicrobial and anti-tumor radiosensitizing drugs effects of reduced

misonidazole on DNA, Int. J. Radiat Biol. 1979; 36: 367-377.

Sugahara, T. and Nakatsugawa, S. Radiation sensitization studies in Japan. Cancer Treatment

Rev. 1981; 8: 51-61.

Ciosek, C.P., Ortel, R.W., Thanass, M.M. and Newcombe, D.S. Indomethacin potentiates PGE2

stimulated cyclic AMP accumulation in human synoriocytes. Nature London, 1974; 251: 148-151.

Hail, V., Horokova, S., Shaff, R.E. and Beaven, M.A. Alteration of tumor growth by aspirin and

indomethacin: Studies with two transplantable tumors in mouse. Eur J Pharmacol. 1976; 37: 367-

Karamali, R. Prostaglandins and cancer: A review. Prostaglandins and Medicine, 1980; 5: 11-28.

Kantor, H.S. and Hampton, M. Indomethacin in submicromolar concentrations inhibits cyclic

AMP-dependent protein kinase. Nature, 1978; 276: 841-842.

Magluilo, E., Genzi-Cipelli, R., Lago, A., Azzini, M., Mogin, E. and Gallico, S. Inhibition effect of

non-steroidal anti-inflammatory drugs on the chemotaxis of human leukocytes in vitro. Int J Clin

Pharmacol Biopharm, 1977; 15: 417-418.

Bennett, A., Charlier, E.M., McDonald, A.M., Simpson, J.S., Stamford, K.E. and Zebro, T.

Prostaglandins and breast cancer. Lancet, 1977; 2: 624-626.

Higgs, G.A., Eakins, K.E., Mugridge, S., Moncada, S. and Vane, J.R. The effect of non-steroid

anti-inflammatory drugs on leukocyte migrations in carrageenan- induced inflammation. Eur J

Pharmacol. 1980; 66: 81-86.

Maderazo, E.G., Breaux, S.B. and Woronick, C.L. Inhibition of human polymorphonuclear

leukocyte cell responses by Ibuprofen. J Phar Sci. 1984; 73: 1403-1406.

Sykes, J. and Maddox, I. Prostaglandin production by experimental tumors and effect of antiinflammatory compounds. Nature (New Biol). 1972; 237: 59-63.

Saez, J.M., Evain, D. and Gallet, D. Role of cyclic AMP and protein kinase on the steroidogenic

action of ACTH, prostaglandin El and dibutyryl cyclic AMP in normal adrenal cells and adrenal

tumor cells from humans. J Cyclic Nucleotide Res. 1978; 4: 311-321.

Horrobin, D.F. Prostaglandins: Physiology, pharmacology and clinical significance. Montreal,

Canada, Eden Press, 1978; 157.

Santaro, M.G., Philpott, G.W. and Jaffe, B.M. Inhibition of tumor growth in vivo and in vitro by

prostaglandin E. Nature 1976; 263: 777-779.

Goodwin, J.S. and Webb, D. Regulation of the immune response by prostaglandins. Clinical

Immun Immunopath. 1980; 15: 106-122.

Goodwin, J.S. Prostaglandin E and cancer growth: Potential for immunotherapy with

prostaglandin synthetase inhibitors. In: Hersh EM, Chirigos MA, Mastringelo MJ, eds.

Augmenting Agents in Cancer Therapy: Progress in Cancer Research and Therapy. 1981; 16: