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New Anticancer Agents in Clinical Development

New Anticancer Agents in Clinical Development

ABSTRACT: A better understanding of the biology and biochemistry of the cancer cell has led to the development of various promising new antineoplastic compounds that are now undergoing phase I, II, and III clinical testing. These drugs include topoisomerase I inhibitors, such as camptothecin and its analogs 9-aminocamptothecin, irinotecan, and topotecan; the paclitaxel analog docetaxel; gemcitabine, an antimetabolite structurally related to cytarabine; and fluorouracil prodrugs and other thymidylate synthase (TS) inhibitors. Another exciting approach to cancer treatment is the use of agents that induce a less malignant state by altering cellular phenotype. Such agents include angiogenesis inhibitors, differentiating agents, signal transduction inhibitors, and gene therapy. [ONCOLOGY 9(11):1191-1199, 9(12):1321-1337, 1995]

Introduction

The 1990s is an exciting decade for oncologists. Intensive research
and development programs during the 1980s and 1990s have resulted
in new anticancer agents with unique mechanisms of action and
significant clinical activity. Recently, three such agents were
approved by the FDA: paclitaxel (Taxol), all-trans-retinoic acid,
and vinorelbine (Navelbine). These agents have shown significant
clinical activity in patients with refractory tumors, such as
non-small-cell lung cancer, platinum-refractory ovarian cancer,
and anthracycline-refractory breast cancer.

This article will review other promising compounds currently in
clinical development. These drugs, which include topoisomerase
I inhibitors, docetaxel (Taxotere), gemcitabine (Gemzar), and
thymidylate synthase (TS) inhibitors, have significant preclinical
activity and are now undergoing phase I, II, and III clinical
testing. The hope is that these novel compounds represent the
first of a long line of new agents developed as a result of our
better understanding of the biology and biochemistry of the cancer
cell.

Topoisomerase I Inhibitors

Topoisomerase I inhibitors are an exciting new class of antineoplastic
agents currently undergoing clinical testing. These compounds
are structurally related to camptothecin, a natural product isolated
from the Chinese plant Camptothecin accuminata [1].

Topoisomerase I is a cellular enzyme involved in maintaining the
topographic structure of DNA during translation, transcription,
and mitosis [2]. The double helix structure of DNA creates torsional
strain in a cell that must be overcome in order for replication
and translation to proceed. DNA topoisomerases control and modify
the topological state of DNA by creating a transient break in
a single strand (topoisomerase I) or both complementary strands
(topoisomerase II) of the DNA backbone [3]. These enzymes are
capable of catalyzing many types of interconversions between DNA
topological isomers. Examples of interconversions include catenation
(interlocking of DNA circles) and decatenation, and knotting (passing
one double strand of DNA through another strand) and unknotting
[3].

It is now established that transient breakage of the DNA backbone
by topoisomerases is accompanied by the formation of a covalent
enzyme-DNA intermediate called the cleavable complex [4]. Inhibition
of topoisomerase I by camptothecin and its analogs is accomplished
by stabilization of the enzyme-DNA cleavable complex. This occurs
after the cleavage step and causes the DNA and topoisomerase to
be trapped in the cleavable complex. When camptothecin is removed,
the DNA is reannealed (ie, the DNA backbone is resealed), and
replication can proceed. Thus, inhibition of topoisomerase I blocks
cellular RNA and DNA synthesis. The mechanism by which topoisomerase
I inhibitors cause cell death is presently unknown [5].

Camptothecin

During extensive screening of random plant products by the Cancer
Chemotherapy National Service Center in the late 1950s, a crude
extract of C accuminata was found to have anticancer activity
[1]. In 1966, Wall and coworkers [1] isolated this extract, camptothecin
(Figure 1), which demonstrated significant anticancer activity
in L1210 leukemia and Walker 256 carcinosarcoma [6,7]. In preclinical
studies, hemorrhagic enterocolitis was the major dose-limiting
toxicity [8].

Phase I and II Trials--In the late 1960s and early 1970s,
camptothecin sodium underwent phase I and phase II testing. Phase
I studies were performed using various dosing schedules: single-dose
[8], daily [9], weekly [9], and daily for 5 days [10]. Although
5 of 18 patients demonstrated objective tumor responses to the
drug in one phase I trial, phase II studies in patients with melanoma
[11] and adenocarcinoma of the colon [12] were limited by severe
hemorrhagic cystitis and unpredictable myelosuppression. As a
result, further clinical development of camptothecin sodium was
halted.

Development of Analogs--It wasn't until the 1980s, when
inhibition of topoisomerase I was identified as the mechanism
of action of camptothecin, that interest in this class of compounds
was rekindled. In addition, it was found that the lactone ring
(E-ring, which is pH labile) was critical to the activity of camptothecin,
and thus the sodium salt used in earlier trials (which mainly
comprised the carboxylate [inactive] form) might have been the
reason for the lack of antitumor activity observed [13].

Structure-activity studies [14] revealed that modification of
the A-ring improved water solubility and reduced protein binding.
Therefore, analogs of camptothecin with increased water solubility
and decreased protein binding were developed, with the anticipation
that such modifications would enhance activity while decreasing
the hemorrhagic cystitis and unpredictable myelosuppression. Currently,
camptothecin and four of its analogs are in clinical development:
9-aminocamptothecin (Figure 1), GI147211, irinotecan (CPT-11),
and topotecan.

Oral Camptothecin--Camptothecin is undergoing evaluation
as an oral preparation. Giovanella and Natelson reported the preliminary
results of a trial with oral camptothecin in which the dose-limiting
toxicity was gastrointestinal [15]. In the 52 patients treated,
5 partial responses and 1 complete response were noted.

9-Aminocamptothecin

9-Amino-20(S)-camptothecin (9-AC) has demonstrated significant
preclinical activity. In studies conducted at the National Cancer
Institute that measured DNA strand breaks and cytotoxicity against
HT-29 cell lines, 9-AC was found to be slightly more potent than
topotecan and significantly more potent than CPT-11, but slightly
less potent than SN-38 (the active metabolite of CPT-11) and camptothecin.

Clinical development of 9-AC has proceeded slowly due to its relative
water insolubility. In a phase I study of 9-AC administered as
a 72-hour continuous infusion in patients with solid tumors, dose-limiting
neutropenia occurred at 59 mcg/m²/h [16]. Other toxicities
(all grade 2) included nausea, vomiting, mucositis, and diarrhea.
Further dose escalation in combination with granulocyte colony-stimulating
factor (G-CSF, filgrastim; Neupogen) is currently under study.

GI147211

GI147211 is a new water-soluble analog of camptothecin. In human
tumor xenograft models HT-29 and SW-48 (colon), PC-3 (prostate),
and MX-1 (breast), GI147211 was 1.5 to 1.8 times more active than
topotecan in suppressing growth. GI147211 has also been found
to be 2.3 to 4.3 times more potent in inhibiting topoisomerase
I activity than topotecan [17].

Based on its preclinical activity, GI147211 has recently undergone
clinical testing with two dosing schedules: daily doses for 5
days and a 72-hour continuous infusion every 21 days. Reversible
grade 3 and 4 neutropenia and thrombocytopenia have been observed
with both schedules [18]. Phase II trials are underway using the
daily for 5 days schedule.

Irinotecan

The initial preclinical and clinical development of irinotecan
(CPT-11) was conducted primarily in Japan. In preclinical testing,
irinotecan was found to be active against a broad spectrum of
tumor models [19]. However, the decarboxylated metabolite SN-38
(7-ethyl-10-hydroxy-camptothecin; Figure 1) plays a major role
in the antitumor activity of irinotecan in vivo [20].

The maximum tolerated dose (MTD) of irinotecan depends on the
dose and schedule, with diarrhea and neutropenia being the major
toxicities. Schedules employing a daily dosing schedule have demonstrated
more neutropenia, whereas intermittent schedules have been associated
with significant diarrhea [21]. The dose intensity on all the
schedules has been approximately 100 mg/m²/wk [21]. However,
in a recently published study from France [22], escalation of
the irinotecan dose was accomplished by means of aggressive treatment
of the diarrhea with antimotility agents. An MTD of 600 mg/m²
given over 90 minutes every 3 weeks was reported, with neutropenia
being dose-limiting.

Diarrhea--Irinotecan has been associated with two forms
of diarrhea. The first type occurs during or just after the infusion
and has a cholinergic mecha nism. The use of atropine at the onset
of this early diarrhea is an effective treatment.

The second type of diarrhea begins 3 to 5 days after the irinotecan
infusion and may be moderate to severe in 20% of patients. Aggressive
treatment at the onset with antimotility agents may obviate its
severity. If late diarrhea is not treated early, it usually runs
a 5- to 7-day course. The mechanism of this type of diarrhea is
unknown, but it may be secondary to the biliary excretion of SN-38,
the active metabolite of irinotecan [23].

Other Toxicities--In addition to dose-limiting myelosuppression
and diarrhea, other toxicities reported with irinotecan include
anemia, transaminasemia, anorexia, alopecia, malaise, flushing,
stomatitis, pneumonitis, nausea, and vomiting. These toxicities
are mild to moderate in severity and reversible [21].

Antitumor Activity--Single-agent activity of irinotecan
has been evaluated in a number of tumor types, including non-Hodgkin's
and Hodgkin's lymphoma, acute leukemia, colon cancer, non-small-cell
and small-cell lung cancer, ovarian cancer, cervical cancer, breast
cancer, pancreatic cancer, and gastric cancer (Table 1). The encouraging
activity of this agent seen in patients with refractory tumors,
such as cervical cancer and colon cancer, has stimulated large
phase II trials now being conducted in the United States and abroad.

Irinotecan Combinations--Because of the novel mechanism
of action and clinical activity of irinotecan, investigators have
explored its use in combination with other cytotoxic agents. In
vitro and in vivo testing of camptothecin analogs has demonstrated
synergistic activity when combined with topoisomerase II inhibitors,
alkylating agents, platinum compounds, and radiation [24].

Phase I trials of several irinotecan combinations have been initiated.
Impressive activity has been demonstrated when irinotecan is combined
with cisplatin (Platinol) or etoposide (VePesid) in patients with
non-small-cell lung cancer. In untreated patients with non-small-cell
lung cancer, response rates to irinotecan-cisplatin have ranged
from 43% to 45% [44,45]. These results have prompted further investigation
of this combination.

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