Recent Food and Drug Administration approval of the camptothecin
analog irinotecan (CPT-11 [Camptosar]) for the treatment of
colorectal cancer resistant to fluorouracil (5-FU) has opened a
new chapter in chemotherapeutic radiation sensitization. High
interest in using this and other camptothecins (eg, topotecan
[Hycamtin], 9-aminocamptothecin) in combination with irradiation is
based in part on past successes with 5-FU, an antimetabolite, as a
radiation sensitizer. Both camptothecin analogs and
antimetabolites have cytotoxic activity against S-phase cells, and
both have a defined role in the treatment of colorectal cancer, a
disease in which radiation sensitization has improved locoregional
control and overall survival.
Radiation sensitization with either class of agents is dose- and
schedule-dependent, and the importance of the timing of
administration of these drugs when given with fractionated
irradiation is a new factor that is gaining attention. This knowledge
combined with new laboratory data will be important in the design of
new camptothecin radiosensitizer trials.
The molecular basis for the lethal effects of ionizing radiation
alone include the production of single- and double-strand breaks in
DNA. Another basic observation regarding repair of x-ray- or
chemotherapeutic-induced genomic damage is the requirement for
topoisomerase I, which is widely used in DNA metabolism.
In the presence of camptothecin, the camptothecin-topoisomerase I-DNA
complex becomes stabilized because the 5¢-phosphoryl terminus of
an enzyme-catalyzed DNA single-strand break is bound covalently to a
tyrosine of topoisomerase I. Irradiation can create thousands of
single-strand breaks per cell per gray, leaving these sites to be
attacked by topoisomerase I in the presence of camptothecin. The rate
of topoisomerase I binding to nicked DNA is also more rapid
(increased by a factor of 800 to 1,000) than its binding rate to
undamaged supercoiled DNA.[7,8] These stabilized complexes interact
with the advancing replication fork during S-phase or during
unscheduled DNA replication after genomic stress and cause the
conversion of single-strand breaks into irreversible DNA
double-strand breaks, resulting in cell death (Figure
Topoisomerase I may also compete with DNA repair complexes (DNA
ligases, poly-(adenosine diphosphate)-ribosyl-transferase) for the
single-strand breaks. In the presence of camptothecins, this can
result in unrepaired DNA damage that can be recognized by the p53
damage-sensing pathway, initiating and possibly amplifying the
apoptotic pathway of cell death.[7,10-12] The camptothecins have also
been found to modulate apoptosis independently of DNA synthesis in
postmitotic neurons and confluent cell cultures, as well as
in actively proliferating cell cultures and in murine tumors in vivo.
High levels of topoisomerase I are associated with a high frequency
of cleavable complex formation. High topoisomerase I levels have
been detected in surgical specimens from malignant melanoma, colonic,
ovarian, esophageal, breast, stomach, and lung cancers, and in
cultures from non-Hodgkins lymphoma and leukemia cells. One
basis for selective camptothecin toxicity in malignant cells compared
to normal tissues may relate to these enzyme levels. An additional
biological basis for selective camptothecin activity is the low pH
found in cancers that can stabilize the closed (active) lactone ring form.[17,18]
In addition, DNA-topoisomerase I-camptothecin cleavable complexes
affect the repair of potentially lethal damage in plateau phase cells (Figure
1). In contrast, in log phase cells, lethality caused by
camptothecin and irradiation also appears to be determined by effects
on the cell cycle; ie, there appears to be differential phase
specificity of cell killing by drug and irradiation. The
camptothecins are considered to be S-phase agents since selective
cytotoxicity is observed in S-phase,[14,16,18,19] while G1-,
G2-, and M-phase cells are relatively spared following
pulse exposure to camptothecin. Elimination by aphidocolin of
camptothecin-induced cytotoxicity and radiation sensitization is
consistent with these S-phase-selective effects.
An additional contribution to radiation sensitization by combination
treatment may be the synchronizing effect of irradiation itself that
preferentially kills G2- through M-cells, thus leaving
S-phase cells intact and subject to attack by camptothecin.[14,19]
The clinical basis for chemoradiation is cytotoxic cooperation
between systemic chemotherapy and irradiation when chemotherapeutic
drugs are given concurrently with fractionated irradiation. Clinical
research has established the superiority of fractionated irradiation,
which spares late toxic effects. When S-phase-specific agents are
administered with conventional irradiation (eg, 2 Gy/d), this regimen
becomes a form of accelerated treatment. With such regimens, the
dose-limiting toxicity may consist not only of the late morbidity of
irradiation (eg, fibrosis and necrosis) but also enhanced acute
toxicity expressed in the rapidly proliferating cell compartments.
Thus, the pattern of dose application used in camptothecin radiation
sensitization studies will likely play a role in their success or failure.
Topotecan is a water-soluble topoisomerase I inhibitor with cytotoxic
activity in a variety of preclinical models. Topotecan exhibits
schedule-dependency in vivo and has high cytotoxic activity with
frequently repeated (daily) dosing schedules.[22,23]
In murine systems, there is evidence that reducing the dose intensity
(by prolonging the drug administration schedule using a small amount
with each treatment) provides a therapeutic advantage because of
reduced host toxicity and equal or superior tumor responses. In
clinical studies, the short plasma half-life of topotecan also
suggests that prolonged drug exposure by infusion could be
effective. In a phase I trial, an escalating low-dose topotecan
infusion was found to have an increased therapeutic ratio when
compared to an intermittent dosing schedule. Neutropenia is
usually the dose-limiting toxicity of topotecan.
Phase II studies have shown that topotecan alone has cytotoxic
activity in lung cancer with intermittent (daily × 5 every 21
days) dosing schedules, as well as in lung cancer patients with
topoisomerase II-refractory disease. In advanced head and neck
cancer patients, topotecan is well-tolerated and has single-agent
activity similar to that of cisplatin (Platinol), 5-FU, and methotrexate.
Decreased production or mutation of topoisomerase I can cause
resistance to the cytotoxic effects of topotecan and other
camptothecins. Active efflux of the camptothecins by
P-glycoprotein-mediated transport may also contribute to resistance.
Radiation Sensitization--Topotecan has demonstrated
radiation-sensitizing properties in log and plateau phase cell
cultures[29,30] and in murine fibrosarcomas in vivo.[31,32] Clinical
trials have begun in patients with non-small-cell lung cancer and in
patients with central nervous system tumors.
Clinical evidence of radiation sensitization with topotecan has been
demonstrated in a dose-escalation trial in patients with locally
advanced, inoperable non-small-cell lung cancer.. In this trial,
12 patients received 60 Gy (2 Gy/d) of radiation plus topotecan
delivered by bolus injection on days 1 through 5 and on days 22
through 26, beginning on the same day as irradiation. The initial
dose level of topotecan was 0.5 mg/m²; dose levels of 0.75 and
1.0 mg/m² were also tested. Doses higher than 0.5 mg/m²
were associated with relatively high acute hematologic and
Of the 12 patients, 5 survived (2 without evident disease) and 7 died
of their cancer. Severe late pulmonary toxicity was not reported, but
pneumonitis was noted.
The Radiation Therapy Oncology Group (RTOG) is evaluating topotecan
plus cranial irradiation in patients with glioblastoma multiforme.
The Childrens Cancer Group (CCG) is also evaluating this
combination in children with pontine gliomas. In both of these
trials, topotecan is given daily as a 30-minute infusion 30 to 120
minutes before irradiation.
1. Rothenberg ML: Current status of irinotecan (CPT-11) in the United
States, in The Camptothecins from Discovery to the Patient, p 272.
New York, New York Academy of Sciences, 1996.
2. Rich TA: Irradiation plus 5-fluorouracil: Cellular mechanisms of
action and treatment schedules. Sem Radiat Oncol 7:267-273, 1997.
3. OConnell MJ, Martenson JA, Wieand HS, et al: Improving
adjuvant therapy for rectal cancer by combining protracted-infusion
fluorouracil with radiation therapy after curative surgery. N Engl J
Med 331:502-507, 1994.
4. Byfield JE, Calabro-Jones P, Klisak I, et al: Pharmacologic
requirements for obtaining sensitization of human tumor cells in
vitro to combined 5-Fluorouracil or ftorafur and X rays. Int J Radiat
Oncol Biol Phys 8:1923-1933, 1982.
5. Hall EJ: DNA strand breaks and chromosomal aberrations.
Radiobiology for the Radiologist p 16, Philadelphia, Lippincott, 1994.
6. Pommier Y: DNA topoisomerase I and II in cancer chemotherapy:
Update and perspectives. Cancer Chemother Pharmacol 32:103-108, 1993.
7. Boothmann DA, Fukunada N, Wang M: Down-regulation of topoisomerase
1 in mammalian cells following ionizing radiation. Cancer Res 54:
8. McCoubrey WK Jr, Champoux JJ: The role of single-strand breaks in
the catenation reaction catalyzed by the rat type I topoisomerase. J
Biol Chem 261(11): 5130-5137, 1986.
9. Iliakis G: Radiation-induced potentially lethal damage: DNA
lesions susceptible to fixation. Int J Radiat Biol 53:541-584, 1988.
10. Lamond J, Wang M, Kinsella T, et al: radiation lethality
enhancement with 9-amino camptothecin: Comparison to other
topoisomerase 1 inhibitors. Int J Radiat Onc Biol Phys
11. Nelson WG, Kastan MB: DNA strand breaks: The DNA template
alterations that trigger p53-dependent DNA damage response pathways.
Mol Cell Biol 14:1815-1823, 1994.
12. Tisher RB, Calderwood CN, Colemann C, et al: Increases in
sequence specific DNA binding by p53 following treatment with
chemotherapeutic and DNA damaging agents. Cancer Res 53:2212-2216, 1993.
13. Morris EJ, Geller HM: Induction of neuronal apoptosis by
camptothecin, an inhibitor of DNA topoisomerase 1: Evidence for cell
cycle independent toxicity. J Cell Biol 134:757-770, 1996.
14. Del Bino G, Bruno S, Yi PN, et al: Apoptotic cell death triggered
by camptothecin or teniposide. The cell cycle specificity and effects
of ionizing radiation. Cell Prolif 25:537-548,1992.
15. Meyn RE, Stephens LC, Hunter NR, et al: Apoptosis in murine
tumors treated with chemotherapy agents. Anticancer Drugs 6: 443-450, 1995.
16. Pommier M: Eucaryotic DNA topoisomerase I: Genome gatekeeper and
its intruders, camptothecins. Semin Onc 23(suppl 3): 3-10, 1996.
17. Potmesil M: Camptothecins: From bench research to hospital wards.
Cancer Res 54:1431-1439, 1994.
18. Slichenmyer WL, Rowinsky EK, Donehower RC, et al: The current
status of camptothecin analogues and antitumor agents. J Natl Cancer
Inst 85:271-291, 1993.
19. Hennequin C, Giocanti N, Balosso J, et al: Interaction of
ionizing radiation with topoisomerase I poison camptothecin in
growing V-79 and HeLa cells. Cancer Res 54:1720-1728, 1994.
20. Falk SJ Smith PJ: DNA damaging and cell cycle effects of the
topoisomerase 1 poison camptothecin in irradiated human cells. Int J
Radiat Biol 61(6): 749-757, 1992.
21. Rich TA: Chemoradiation or accelerated fractionation: Basic
considerations. J Infus Chemother 1:2-8, 1992.
22. Slichenmyer WJ, Rowinsky EK, Donehower RC, et al: The current
status of camptothecin analogues as antitumor agents. J Natl Cancer
Inst 85:271-291, 1993.
23. Houghton PJ, Stewart CF, Zamboni WC, et al: Schedule-dependent
efficacy of camptothecin in models of human cancer. In: The
Camptothecius: From Discovery to the Patient, volume 803 p 188. New
York, New York Academy of Sciences, 1996.
24. ODwyer PJ, LaCreta FP, Haas NB, et al: Clinical,
pharmacokinetic and biological studies of topotecan. Cancer Chemother
Pharmacol 34(suppl):S46-S52, 1994.
25.Perez-Soler R, Glisson BS, Lee JS, et al: Treatment of patients
with small-cell lung cancer refractory to etoposide and cisplatin
with the topoisomerase I poison topotecan. J Clin Oncol 14:2785-2790, 1996.
26. Perez-Soler R, Fossella FV, Glisson BS, et al: Phase II study of
topotecan in patients with advanced non-small-cell lung cancer
previously untreated with chemotherapy. J Clin Oncol 14:503-513, 1996.
27. Robert F, Soong SJ, Wheeler RH: A phase II study of topotecan in
patients with recurrent head and neck cancer: Identification of an
active new agent. Am J Clin Oncol 20:298-302, 1997.
28. Murren JR, Beidler DR, Cheng YC: Camptothecin resistance related
to drug-induced down-regulation of topoisomerase I and to steps
occurring after the formation of protein-liked DNA breaks. In: The
Camptothecius: From Discovery to the Patient, p 74. New York, New
York Academy of Sciences, 1996.
29. Lamond JP, Wang M, Kinsella TJ, Boothman DA: Concentration and
timing dependence of lethality enhancement between topotecan, a
topoisomerase I inhibitor, and ionizing radiation. Int J Radiat Oncol
Biol Phys 36:361-368, 1996.
30. Mattern MR, Hoffman GA, McCabe FL, et al: Synergistic cell
killing by ionizing radiation and topoisomerase I inhibitor topotecan
(SK&F 104864) Cancer Res 51:5813-5816, 1991.
31. Kim JH, Kim SH, Kolozsvary A, et al: Potentiation of radiation
response in human carcinoma cells in vitro and murine fibrosarcoma in
vivo by topotecan, an inhibitor of DNA topoisomerase I. Int J Radiat
Biol Oncol Phys 22:515-518,1992.
32. Boscia RE, Korbut T, Holden SA, et al: Interaction of
topoisomerase I inhibitors with radiation in cis-diamminecholoroplatinum
(II)-sensitive and -resistant cells in vitro and in the FSAIIC
fibrosarcoma in vivo. Int J Cancer 53:118-123,1993.
33. Graham MV, Jahanzeb M, Dresler CM, et al: Results of a trial with
topotecan dose escalation and concurrent thoracic radiation therapy
for locally advanced, inoperable non-small-cell lung cancer. Int J
Radiat Oncol Biol Phys 36:1215-1220, 1996.
34. Wiseman LR, Markham A: Irinotecan: A review of its pharmacologic
properties and clinical efficacy in the management of advanced
colorectal cancer. Drugs 52:606-621, 1996.
35. Conti JA, Kemeny NA, Saltz LB, et al: Irinotecan is an active
agent in untreated patients with metastatic colorectal cancer J Clin
Oncol 14:709-715, 1996.
36. Shimada Y, Rougier P, Pitot H: Efficacy of CPT-11 as a single
agent in metastatic colorectal cancer. Eur J Cancer 32A(suppl
37. Gupta E, Wang X, Ramirez J, et al: Modulation of glucuronidation
of SN-38, the active metabolite of irinotecan, by valproic acid and
phenobarbital. Cancer Chemother Pharmacol 39:440-444,1997.
38. Takasuna K, Hagiwara T, Hirohashi M, et al: Involvement of
beta-glucuronidase in intestinal microflora in the intestinal
toxicity of the antitumor camptothecin derivative irinotecan
hydrochloride (CPT-11) in rats. Cancer Res 56:3752-3757, 1996.
39. Araki E, Ishikawa M, Logo M, et al: Relationship between
development of diarrhea and the concentration of SN-38, an active
metabolite of CPT-11, in the intestine and the blood plasma of
athymic mice following intraperitoneal administration of CPT-11. Jpn
J Cancer Res 87:697-702, 1993.
40. Muggia FM, Dimery I, Arbuck S: Camptothecin and its analogs: An
overview of their potential in cancer therapeutics. In: The
Camptothecius: From Discovery to the Patient, p. 213, New York, New
York Academy of Sciences, 1996.
41. Takaoka K, Ohtsuka K, Jin M, et al: Conversion of CPT-11 to its
active form, SN-38, by carboxylesterase of non-small-cell lung cancer
(abstract). Proc Am Soc Clin Oncol 16:252a, 1997.
42. Tamura K, Takada M, Kawase I, et al: Enhancement of tumor
radio-response by irinotecan in human lung tumor xenografts. Jpn J
Cancer Res 88:218-223, 1997.
43. Omura M, Torigoe S, Kubota N: SN-38, a metabolite of the
camptothecin derivative CPT-11, potentiates the cytotoxic effects of
radiation in human colon adenocarcinoma cells grown as spheroids.
Radiother Oncol 43:197-201, 1997.
44.Kudoh S, Kurihara N, Okishio K, et al: A phase I/II study of
weekly irinotecan (CPT-11) and simultaneous thoracic radiotherapy for
unresectable locally advanced non-small cell lung cancer (abstract).
Proc Am Soc Clin Oncol 15:372, 1996.
45. Saka H, Shimokata K, Yoshida S, et al: Irinotecan and concurrent
radiotherapy in locally advanced non-small-cell lung cancer: A phase
II study of Japan Clinical Oncology Group (JCOG9504) (abstract). Proc
Am Soc Clin Oncol 16:447a, 1997.
46. Saltz L, Early E, Kelsen D, et al: Phase I study of chronic daily
low-dose irinotecan (abstract). Proc Am Soc Clin Oncol 16:200a, 1997.
47. Lamond JP, Wang M, Kinsella TJ, et al: Radiation lethality
enhancement with 9-aminocamptothecin: Comparison to other
topoisomerase I inhibitors. Int J Radiat Biol 36:369-376, 1996.
48. Kirichenko AV, Rich TA, Newman RA, et al: Potentiation of murine
MCA-4 carcinoma radioresponse by 9-amino20(S)-camptothecin. Cancer
49. Sheving LE, Sheving LA, McClellan JL, et al: Experimental basis
for circadian cancer chemotherapy. J Infus Chemother 5:3-7, 1995.
50. Levi FA, Zidani R, Vannetzel J-M, et al: Chronomodulated vs
fixed-infusion-rate delivery of ambulatory chemotherapy with
oxaliplatin, fluorouracil, and folinic acid (leucovorin) in patients
with colorectal cancer metastasis: A randomized multi-institutional
trial. J Natl Cancer Inst 86:1608-1617, 1994.
51. De W. Marsh R, Chu N-M, et al: Preoperative treatment of patients
with locally advanced unresectable rectal adenocarcinoma utilizing
continuous chronobiologically shaped 5-fluorouracil infusion and
radiation therapy. Cancer 78:217-225,1996.
52. Weinstein GD, Rich TA, Shumate CR, et al: Preoperative infusional
chemoradiation and surgery with or without an electron beam
intraoperative boost for advanced primary rectal cancer. Int J Radiat
Oncol Biol Phys 32:197-204, 1995.
53. Thames H, Ruifrok A, Mason K: The effect of proliferative status
and clonogen content on the response of jejunal crypts to split-dose
irradiation. Radiat Res 147:172-179, 1997.
54. Filipski E, Levi F, Vardot N, et al: Circadian changes in
irinotecan toxicity in mice. Proc Am Acad Cancer Res 38:305, 1997.
55. Ohdo S, Makinosumi T, Ishizaki T, et al: Cell cycle-dependent
chronotoxicity of irinotecan hydrochloride in mice. J Pharmacol Exp
Ther 283:1383-1388, 1997.