Chapter 16. Radiosensitizers

Chapter 16. Radiosensitizers Mark J. Suto Parke-Davis Pharmaceutical Research Division Warner-Lambert Company Ann Arbor, Michigan 48105 Introduction - Radiation therapy continues to be an important treatment modality for many forms of human cancer. Although this therapeutic approach is effective in many cases, normal tissue toxicity limits the total dose of radiation a patient can ultimately receive. Also, many tumors contain areas of diminished oxygen concentration which make them more resistant to the lethal effects of radiation. Advances in instrumentation and technology have provided radiotherapists with the means of targeting x-rays more precisely and eliminating some of the normal tissue damage, but not enough to eliminate the problem totally. Since the number of patients diagnosed with cancer will exceed one million in 1990, and 50-60% of these patients will undergo some type of radiation treatment, methods which increase the effectiveness of clinical radiotherapy are potentially very useful (1). Fortunately, physiological differences that exist between tumor cells and normal tissues have been exploited to develop a number of clinical candidates. However, most of these compounds have failed due to a lack of potency or as a result of direct toxicity of the drug at therapeutic doses (2). These studies, although clinically unsuccessful, have provided a great deal of information which has been useful in the design and development of new approaches and agents (3). This chapter will review progress toward enhancing the effectiveness of radiotherapy. It will cover the use of chemical agents which, through a variety of mechanisms, selectively sensitize tumors to the lethal effects of x-rays. Since this is the first time that radiosensitizers have been covered in this forum, an effort has been made not only to include the most recent literature, but where appropriate, to include previous references which illustrate a novel or interesting approach. A number of recent reviews address in more detail the topics highlighted above (4), the rationale for the development of such compounds (5),potential mechanisms and points of intervention (S), as well as the clinical aspects of radiobiology (7). A variety of methods have been evaluated in attempts to overcome the radioresistanceof tumor cells. The most widely studied approach includes the use of oxygen mimetics, which are compounds with specific physical properties (reduction potential, pKa and log P) that are able to penetrate into tumors and cause DNA damage by a mechanism similar to that of oxygen. Also under evaluation are modifiers of oxygen utilization which increase the oxygen concentration in tumors or inhibit its metabolic use, and repair inhibitors, which are compounds that interfere with the processes involved in the repair of radiation-induced DNA damage. Oxvaen Mimetics - A large number of nitroheterocycleshave been evaluated as oxygen mimetics, although some work has been done in an attempt to find non-nitro compounds acting via the same mechanism (8-10). However, many of the non-nitro compounds evaluated were quickly metabolizedand therefore not activebin. Of the nitroheterocyclesstudied, the 2-nitroimidazoles exhibited the best overall properties, which could not be explained solely on the basis of their reduction potentials (11). Many of the compounds evaluated clinically are of this class with etanidazole (SR 2508,J) and pimonidazole (Ro-03-8799.2) still under active evaluation (4-7). A substantial increase in radiosensitizingactivity, b o t h h m a n d h m , was seen when an alkylating moiety was combined with the 2-nitroimidazole (12). An aziridine group was substituted for the methoxy group of misonidazole Q) to produce RSU 1069 (4). This was the first "DNA-targeted'' radiosensitizerto be studied clinically; however, the reactivity of the aziridine led to unmanageable emesis and the compound was dropped (13). In an effort to decrease this side effect, yet retain

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the radiosensitizing activity, the aziridine was replaced by substituted aziridines (14), cycloalklylaziridines (15,16), acetohydroxamic acids (17), chloroethylnitrosoureas (18) and ahaloethylamines (19,20). KIH-802 &), the most potent of the acetohydroxamic acid analogs, displayed significant radiosensitizing activity in vivo in SCCVll tumors (21). Pharmacokinetic studies revealed that levels of 5 in neuronal tissue were quite low suggesting that the compound would have a minimal tendency to cause neurotoxicity. Further studies on this compound are progressing as is additional work on other hydroxamic derivatives that can stabilize radicals in a similar manner (17). The use of 6-haloethylamines resulted in two compounds, RB 6145 (fj) and the corresponding desoxy derivative, PD 130908 (7).These aziridine prcdrugs were equal in activity tos, but less toxic (22). Studies to select a potential clinical candidate have been initiated (23). Combining reactive side chains with aza-2-nitroimidazole (3-nitro-l,2,4-triazole)did not result in an increase in radiosensitizng potency as was observed for the 2-nitroimidazoles. Of those anaolgs synthesized the best activity was displayed by compound&, which contained a piperidine moiety (24,25).

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A rationale to increase the selectivity of oxygen mimetics by targeting them to the DNA of hypoxic cells led to the design of compounds combining alkylating moietieswith 2-nitroimidazoles. DNA intercalating groups have also been employed in this fashion. For example, linking a phenanthridine to a nitroimidazole resulted in (NLP-1, 9) that bound to DNA as measured by ethidium bromide displacement, was selectively cytotoxic to hypoxic cells (8-fold) and produced radiosensitization in vitro (26). The radiosensitization observed with this compound was somewhat less than expected and studies are underway to determine if this resulted from reduced drug levels under the test conditions or to a lack of effective targeting. Studies on a series of nitroacridine positional isomers were also reported (27). Nitracrine (KJ) has been shown to be a “DNA-targeted”, hypoxia-selective radiosensitizer (28). Studies on its isomers have demonstrated differences in reduction potential, hypoxic cell cytotoxicity, aerobic toxicity and hydrolytic and reductive stability. The 2,- 3,- and 4-positionalisomers showed similar sensitization, but were less potent than the parent compound, (KJ). These differences have been attributed to the fact that these compounds have higher DNA association constants than lo,indicating that kinetically stable binding of the compounds to DNA prevents the rapid diffusion required to access target molecules.

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Another form of DNA-targeted drug design was illustrated by the use of antibodies directed against tumor cell surface antigens. Earlier studies demonstrated the feasibility of applying this concept (29,30).Recent work has focused on a series of 4-nitro-5-sulfonatoimidazolesas potent

4

agents for conjugationto an antibody targeted to colorectal carcinoma, which, in clinical situations, has frequently been less responsive to radiotherapy than other tumor types (31). The compounds were evaluated in vitro against a human colon adenocarcinoma cell line (SWI 116), and several members of this series were found to be 40-300 times more effective radiosensitizers than misonidazole. The activity of these compounds was not correlated to reduction potential, was )found to have glutathione reactivity, capacity factor, or cytotoxicity. The benzyl derivative (ll the greatest sensitizing efficiency and is presently undergoing stabilization studies for possible antibody attachment (31). A study was conducted whereby the calculated energy of the lowest unoccupied molecular orbital was shown to correlate to the measured reduction potentials and to the in vitro radiosensitizing activity for a series of 5-nitroirnidazoles (32,33). Additional studies were was indeed related to their performed to prove that the activity seen with these compounds (l2) reduction potentials and not to the inhibition of DNA synthesis or other related processes (3435). In an attempt to increase the radiosensitizing activity by raising the reduction potential, a series of 5-nitrofurans &) containing a variety of side chains was synthesized (36). Although these compounds were potent radiosensitizers in vitro, they were, in general, more cytotoxic to oxic cells and were inactive in vivo. This lack of in vivo activity was postulated to result from metabolism, poor distribution and/or other biological interactions that removed the compounds before they could reach the tumors.

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Antitumor platinum complexes, such as cis-platinum have also been shown to be radiosensitizers. They impart their radiosensitizing activity via an oxygen-mimeticmechanismsimilar to that of nitroheterocycles,whereby reduction of the metal occurs resulting in subsequent fixation of the radiation-induced DNA damage (37). They may also sensitize through a number of related mechanisms (38). Platinum complexes have been combined recently with a variety of nitroheterocycles to provide yet another means of delivering a potential sensitizer to its intended target (39).The compounds reported had moderate activity as radiosensitizers both in vitro and -in vivo. They bind to DNA, as measured by the inhibition of restriction enzyme cleavage and their activity was potentiated by the concurrent use of vasodilators. Other metal complexes have also been used as radiosensitizers, specifically in conjunction with porphyrins (40,41). Porphyrins are known to accumulate selectively in some tumors and have been used extensively as photosensitizers. Metal/porphyrin complexes designedto take advantage of this selectivity were prepared and evaluated. Six different metals (Co, Cu, Zn, Fe, Pd, Mn) in combination with substituted porphyrins were investigated. Of those tested, the cobalt complex of tetrakis(4-sulfonatophenyl)porphyrin @) had in vitro activity superior to that of other metals. Additionally, selectivity for hypoxic cells over oxic cells was observed in the radiosensitization studies. A group of non-organic compounds with similar redox properties to the nitroimidazoles was as tested as radiosensitizers. Two ferricinium salts, trichloroacetateand hexafluorophosphate well as an alkyl-substituted analog, 1-pentyl ferricinium hexafluorophosphate, were prepared (42). Only the first two compounds were tested as radiosensitizers since the lipophilic nature of the alkyl analog resulted in considerable toxicity due to increased cellular uptake. Differences in toxicity between oxic and hypoxic cells were observed when serum proteins were added, with oxic cells becoming less susceptibleto the compounds. Moderate radiosensitizing activity was observed and this result, combined with the differential toxicity data, suggested an area for further study.

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In an attempt to eliminate the liabilitiesof nitroimidazoles, other nitroaromaticcompounds have been evaluated for radiosensitizing activity. These include nitrobenzofurazans (43),1-alkyl-3nitropyrrolopyridines (44), 3-nitro-4-quinolones (45) and 3-nitrobenzenesulfonamides (46). This last group of compounds (1818) has been reported extensively in the patent literature as radiosensitizers(46-49).

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SR 4233 a potent and selective hypoxic cell cylotoxin, that caused extensive cell death in the presence of radiation, has been shown recently to be effective in a clinically relevant fractionated radiation protocol (50,51). In vivo studies, using four different tumors varying in their hypoxic fraction, compared to 2. The data indicate that resulted in a significant enhancement of cell killing over radiation alone. In two of the tumors studied, no effect was observed withl, whereas- was effective in all of the tumor systems tested. Since the compound was active when given either prior to or after radiation, it is thought that direct killing of hypoxic cells rather than radiosensitizationwas responsible for its effect. Mice were able to tolerate administration

Radiosensitizers

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of this compound for up to six weeks, and toxicity studies indicated no adverse effects on normal tissues. The preclinical data suggests that this compound has considerable promise as an adjunct to clinical radiotherapy (51).

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Oxvaen Modifiers - Sensitization of tumors can also be achieved by increasing the concentration of oxygen in tumors. The first evaluation of this approach involved the use of hyperbaric oxygen. Clinical trials were conducted, but failed to indicate an enhancement over radiation alone (52). Although the concentration of oxygen in blood was increased, it was unclear whether this resulted in a corresponding increase of oxygen concentrationin the tumors. Perfluorochemicalshave been utilized to increase oxygen- carrying capability of the blood and have been shown to increase the radiosensitivity of mouse tumors. Fluosol-DA. (20%) is currently in Phase 3 clinical trials as a radiosensitizer. Recent animal studies have shown that Fluosol-DA in combination with carbogen breathing (95% oxygen/ 5% carbon dioxide) increases the intratumoral oxygen levels, thereby decreasing the hypoxic fraction (53). Significant radiosensitization of KHT tumors, using a fractionated protocol, was obtained. Additional studies using the laser Doppler technique demonstrated that tumor blood flow was increased with no substantial increase in skin blood flow. Some toxicities have been observed with Fluosol-DAand studies examining other more stable, less toxic perfluorochemicalemulsions are underway. For example, more concentratedemulsions based on bis(perfluorohexy1)ethylene (F66E) and bromoperfluorooctane (PFOB) have been studied in animals (54). These perfluorochemicals carry more oxygen than Fluosol, which contains a mixture of perfluorodecalin and perfluorotripropylamine,and are obtained by chemical syntheses providing a highly purified fluorocarbon. Of interest is the fact that PFOB has a much shorter retention time in organs than other perfluorochemicals (4 days compared to 65 days for Ftripropylamine and 400 days for F66E). These new emulsions had only weak activity as radiosensitizers, but caused no increase in lung metastases and the effect of PFOB at five times the dose on the liver, spleen, lung and overall body weight was no greater than that seen with Fluosol. The decreased toxicity of these compounds warrants further studies in comparative trials with Fluosol. A more concentrated emulsion, Therox 0, containing bis-perfluorobutyl ethylene (F44E), has been evaluated in vivo to determine the effect of changes in the injection volume and/or concentration of the perfluorochemicalon radiation-inducedgrowthdelay of Lewis lung carcinoma (55). The emulsion alone had no effect, but in combination with carbogen breathing, concentrations of the emulsion varying from 48% to 12% (v/v) and injection volumes from 0.4 to 0.1 ml resulted in a substantial increase in growth-delay. The studies indicated that the most important parameter was the injection volume with a dose of 4 mg/kg in a volume of 0.2 ml showing the best activity. An equivalent dose of Fluosol-DA would have to be given in a volume of 0.5 ml resulting in significant stress to the animal.

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Increasingthe blood flow to tumors represents another approach to increasingtheir sensitivity to radiation. The calcium antagonists verapamil, nifedipine and flunarizine, which each modify host blood flow by a different mechanism, were evaluated for their ability to decrease hypoxia and sensitize SCCVll/St tumors to radiation (56). At higher doses verapamil and nifedipine increased cell survival after radiation and increased the hypoxic fraction of the tumor as determined by Hoescht 33342 staining. This radioprotective effect was attributed to the "steal phenomenon", whereby decreases in blood pressure result in a decrease in blood flow to the tumors. At lower doses, the opposite effect was observed. A 30% reduction in the hypoxic fraction was seen, but very at),all doses, produced significant little radiosensitizationaccompaniedthis effect. Flunarizine @O sensitization of the tumor although there was only a 20% reduction in tumor hypoxia. The discrepancy between the reduction in tumor hypoxia and the radiosensitizationseen with these compounds was attributed to the fact that 20 can prevent the occurrence of hypoxia-induced rigidification of red blood cells whereas the other compounds cannot. A closely related, but less I was ) also examined (57). Studies using the Rif-1 tumor, which potent analog, cinarizine & contains a smaller hypoxic fraction than the SCCVll tumor used previously, showed that= was a much weaker sensitizer than 20 in the SCCVll model and was inactive in the Rif-1 tumor. Compound20, which was active in both systems, was assessed for normal tissue toxicity and was found to have no effect on the total white blood cell count. Additional studies using fractionated radiation regimens have been initiated. Indomethacin, has also been evaluated as a radiosensitizer. This compound is a calcium antagonist and reacts with hydroxy radicals to produce a species toxic to cells (58). It was also shown to sensitize fibrosarcomas to radiation (59). Growth delays of nine days for single radiation doses and six days for fractionated doses, with 2/10 cures in each study, were obtained. The exact mechanismfor the activity was not presented, but may result from a combination of all the aforementioned effects. This drug is currently used clinically as an antiinflammatory agent, therefore data regarding metabolism, toxicity and pharmacokinetics are available and should facilitate additional radiosensitizer studies (60). Some chlorophenoxyaceticacid derivatives, which have clinical utility as lipid lowering agents, have also been found to reduce the affinity of hemoglobinfor oxygen (61). This reduced binding to hemoglobin increases the availability of oxygen to hypoxic regions of tumors. The hypoxic

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fraction of SCCVll tumors was reduced by 30-40 fold by treatment with clofibrate resulting in sensitization of these tumors to radiation. Two less toxic analogs, ML1024 (22)and ML1037 (23), had a similar effect on hemoglobin affinity, but displayed very little radiosensitization. Apparently, changes in the hemoglobin affinity, and the resulting increase in plasma oxygen concentration, is not the sole mechanism by which clofibrate sensitizes tumors to radiation. Nicotinamide &4) and pyrazinamide have also been shown to produce small, but significant, changes in tumor blood flow (€2-65). Sensitization studies with a variety of tumor types confirm that these changes in blood flow do result in the senskization of tumors to the lethal effects of radiation. Only a slight effect was seen in normal tissues as assessed by examining mouse crypt cells, indicating a potential therapeutic advantage. Camphor also sensitized tumors to radiation, but by a more general decrease in oxygen consumption by normal cells (66). This made more oxygen available for penetrationinto hypoxic areas. The compound was relatively nontoxic and resulted in significant sensitization of tumors (increased growth-delay) with a number of cures at the higher doses.

- The use of agents which inhibit the repair of radiation-induced DNA damage in the tumor is more complex and less clearly defined than previously discussed areas. A number of enzymatic processes are thought to be involved in DNA repair and which of these are critical has been widely disputed (67). Agents that are classified as repair inhibitors can act by a variety of mechanisms, but usually have in common the fact that they inhibit cellular repair processes after radiation (68). One enzyme believed to regulate or modify the repair of radiation-induced DNA damage is poly(ADP-ribose)polymerase (69). An inhibitor of this enzyme, 3-aminobenzamide@),has been shown to sensitize cells to radiation and inhibit cellular repair processes (61). Originally, it was thought that24 fell into this class of radiosensitizers and that its activity was due to inhibition of this enzyme. However, more recent evidence suggests t h a t s sensitizes tumor cells to radiation solely by virtue of its effect on tumor blood flow (65). Newer compounds postulated to act as repair inhibitors all are structurally related to the benzamides. A series of rigid benzamide analogs, the dihydroisoquinolinones, were shown to be more potent inhibitors of the enzyme than 3aminobenzamide, and exhibited significant post-irradiation sensitization (70-73). One member of this series, PD 128763 @), was also shown to inhibit cellular repair processes, repair of radiationinduced DNA strand breaks and was active & & as a radiosensitizer (74-77). A correlation was seen between inhibition of the enzyme, poly(ADP-ribose)polymerase and inhibition of cellular repair. Additional studies are in progress both to optimize thebin activity and to elucidate further their mechanismof action. A series of 8-aminocarsalarnderivatives (2J$J have been described in a patent as inhibitors of this enzyme and as radiosensitizers (78).

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Section I11 Chemotherapeutic Agents

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Several naphthylsulfonamides were shown to inhibit the repair of radiation-inducedDNA double strand breaks (79). The most active member of the series, which is a 3-substituted benzamide analog @),was active in vivo in EMT6 tumors (400 mg/kg, single dose of radiation) and exhibited a 16 day growth delay over radiation alone in SCCVll tumors. Ouabain, a cardiac glycoside and potent inhibitor of the sodium-potassiumpump, has been shown to radiosensitizetumor cells (A549 adenocarcinoma) selectively over normal cells (CCL-210 lung fibroblast) (80).Evidence for this compound acting as a repair inhibitor stems from the fact that the compound is active post-irradiation. Studies on this promising lead aimed at determining the mechanismof sensitization as well as the reason for the tumor selectivity were inconclusive and are continuing. The effects on potassium retention and protein synthesis were evaluated but found not to contribute to the selective radiosensitization of tumor cells. Miscellaneous - A clinical re-evaluationof the use of halogenated pyrimidines(30) as radiosensitizers was undertaken (81). Previous clinical studies were hampered by normal tissue toxicity and difficulties with drug administration. To be effective, these compounds require incorporation into DNA in place of thymidine, and therefore many days of continuous infusion are required to ensure sufficient levels in the tumors. To support ongoing clinical trials, studies examining the levels of incorporation, methods for modifying these levels, and the effect of various doses of radiation used have been initiated.

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6-Thioguanine (6-TG,1) has been used clinically as an antileukemic agent for over 30 years. Studies aimed at determining whether this compound could sensitize mouse tumors to radiation have been carried out (82). At concentrations readily achievable in humans, sensitized the Meth-A and Rif tumors to radiation in single dose fractionated protocols. In one study, activity was seen w i t h a and radiation, whereas no activity was seen with radiation alone. Also, the compound produced no normal tissue damage over that seen with radiation alone. Although the mechanism of sensitization remains elusive, the data suggest that clinical studies with this compound should be pursued. Five different glyoxals, were evaluated as radiosensitizers in vitro using TC-SV4O cells (83). The phenyl glyoxals showed moderate radiosensitization of hypoxic cells and none of the compounds sensitized aerobic cells. Their effect on cellular levels of nonprotein sulfhydryls was measured, but it was concluded that their weak ability to deplete thiols did not account for their slight radiosensitizingeffect.

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Conclusions - The search for new radiosensitizers has focused on obtaining more selective, less toxic compounds. More recently, approaches have investigated novel means of targeting compounds to DNA, modifying oxidative processes, and inhibiting the repair of radiation-induced DNA damage. Additional mechanistic studies in conjunction with carefully chosen clinical protocols will ultimately prove the utility of these compounds. References 1

2 3 4 5 6 7 8 9 10

11 12 13 14 15 16 17 18 19

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30 31 32 33 34 35 36 37 38 39 40 41 42 43 44

T.L. Phillips in "Clinical Trials in Cancer Medicine", U. Veronesi and G. Bondonna eds., Academic Press, 1985, p 173. S. Dische. Int. J. Rad. Oncol. Biol. Phys..s. 1057 (1989). J.M. Brown in "Modification of Radiosensitivity in Cancer Treatment", T. Sugaharaed. Academic Press, 1984. p 139. C.N. Coleman and A.T. Turrisi, Critical Rev. Oncol/Hemat.a, 225, (1990). T.H. Wasserman and M. Kligerman in "Principles and Practice of Radiation Oncology" C.A. Perez, and L.W. Brady eds., Lippincott, 1987. p 360. A. Rojas and J. Denekarnp, Exper.,s, 41 (1989). M.L. Sutton in "Radiotherapy in Clinical Practice" H.F. Stone, ed. Butterworths, 1986, pp 1. M.A. Shenoy and B.B. Singh, Int. J. Rad. Bio1.,48, 315 (1985). H. Hori, H. Maezawa, Y. litaka. T. Ohsaka, T. Shibata, T. Mori and S.lnayama. Jpn. J. Cancer R e s . , B , 1128 (1987). S. lnayama and T. Mori in "Modification of Radiosensitivity in Cancer Treatment" T. Sugahara ed. Academic Press, 1984, p 109. E. Finklestein and G. Glatstein, 1nt.J. Rad. Oncol. Biol. Phys.14, 205 (1988). I.J. Stratford, 0. O'Neill, P.W. Sheldon, A.R.J. Silver, J. Walling and G.E. Adams, Biochem. Pharmacol., 105 (1986), A. Horwich, S.B. Holiday, J.M. Deacon and M.J. Peckham, Br. J. Rad.,l3, 1238 (1986). P. O'Neill, T.C. Jenkins, I.J. Stratford, A.R.J. Silver, I. Ahmed, S.S. McNeil, E.M. Fielden and G.E. Adams, Anticancer Drug Des.,l, 271, (1987). M.J. Suto and L.M. Werbel, U S Patent 4,797,397 (1989). M.J. Suto, M.A. Steir, J.S. Sebolt, W.R. Leopold, C.M. ArundeCSuto, W.E. Elliott and L.M. Werbel, 198th ACS Meeting, Miami (1989), Abstr. No. Medi 24. H. Hori, C. Marayama, T. Mori, Y. Shibamoto. M. Abe, Y. Onoyama and S. Seiichi. Int. J. Rad. Oncol. Biol. Phys.. 16, 1029 (1989). R.T. Mulcahy, A. Carminati and J. Barascut. J. Imbach, Cancer R e s . , B , 798 (1988). T.C. Jenkins, M.A. Naylor, P. O'Neill, M.D. Threadgill, S. Cole, I.J. Stratford, G.E. Adams, E.M. Fielden, M.J. Suto and M.A. Steir. J. Med. C h e m . , a , 2603, (1990). M.J. Suto, US. Patent 4,954,515 (1990). K. Sasai, Y. Shibamoto, M. Takahashi, L. Zhou, H. Hori, H. Nagasawa, T. Shibata, S. lnayama and M. Abe, Cancer Chem. Pharm..B, 112 (1990). J.S. Sebolt-Leopold, C.M. ArundeCSuto, W.E. Elliott, W.R. Leopold, L.M. Werbel and M.J. Suto, Proc. 38th Radiation Research Society Meeting, New Orleans, Abstr. No. Cv-14, (1990). S. Cole, I.J. Stratford, G.E. Adarns, E.M. Fielden and T.C. Jenkins, Rad. Res.&. s38 (1990). T. Jenkins, I. Stratford and M. Stephens, AntiCancer Drug Des.,q, 145 (1989). Y. Nago, S. Sano, M. Ochiai. K. Fuji, S. Nishimoto. T. Kagiya, C. Murayama, T. Mori. Y. Shibatmoto, K. Sasai and M. Abe, Chem. Pharm. BuII.,Z, 1951 (1989). R. Panicucci, R. Heal, K. Laderoute, D. Cowan, R.A. McClelland and A.M. Rauth, Int. J. Rad. Oncol. Biol. P h y s . , x , 1039, (1989). P.B. Roberts, W.A. Denny, L.P.G. Wakelin, R.F. Anderson and W.R. Wilson, Rad. Res.,m 153 , (1990). P.B. Roberts, R.F. Anderson and W.R. Wilson, Int. J. Rad. Oncol. Biol. Phys.,x, 641 (1987). N.D. Heindel. J.M.A.M. Van Dongen, D.A. Fitzpatrick, B.A. Mease and K.J. Schray. J. Pharm. Sci.76, 384 (1987). K.P. Borlinghaus, D.A. Fitzpatrick. N.D. Heindel, J.A. Mattis. B.A. Mease. K.J. Schray, D.J. Schealy, H.L. Walton and D.V. Woo, Cancer Res.,47, 4071 (1987). D.A. Fitzpatrick, N.D. Heindel, R. Egolf and H.L. Walton, Rad. R e s . , x , 47 (1989). L. Santos, M. Lopez-Zumel, M. Alvarez and M. Izquierdo, Int. J. Rad. Bio1.,55, 983 (1989). L. Santos, M. Cornago. M. Izquierdo, M. Lopez-Zumel and Y.G. Smeyers, Quant. Struct.-Act. Retat.,& 214 (1989). L. Santos, P. Cornago, M. Lopez-Zumel and M. Pintado, Biorned. Biochim. Acta.2. 757 (1989). L. Santos, P. Ramirez and C. Lopez-Zumel, Chem. Biol. Interactions.i'J, 245 (1989). M. Naylor. M. Stephens, s. Cole, M. Threadgill, I. Stratford. P. O'Neill. E. Fielden and G. Adarns, J. Med. Chem.. 33,2508 (1990). L. Dewit, Int. J. Rad. Oncol. Biol. Phys.,s, 403 (1987). N. Farrell, Progress in Clinical Biochemistry.3, 89 (1989). K.A. Skov and D.J. Chaplin, European Patent 0287317 (1988). D.H. Picker, M.J. Abrarns, J.F. Voliano and C.M. Glandomenico, U S Patent 4,851,403 (1989). J.A. OHara, E.B. Douple, M.A. Abrams, D.J. Picker, C.M. Giandomenico and J.F. Vollano, Int. J. Rad. Oncol. Biol. Phys.,>, 1049 (1989). A.M. Joy, D.M.L. Goodgame and I.J. Stratford, Int. J. Rad. Oncol. Biol. Phys.,>, 1053 (1989). E. Fujita, Japanese Patent 54151860 (1986). J. Yi-Zun and I. Stratford, Int. J. Rad. Oncol. Biol. Phys.,s, 357 (1989).

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Section ID-Chemotherapeutic Agents

Plattner, Ed.

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