I guess I'm on the irofulven side here, but I hope that both work - let's see if we can avoid a religious war on this topic though. <g>
Miljenko was a big help to me when I first was trying to understand 9-NC in late 1998, when I first bought some SUPG. Interestingly, 9-NC is a great example of something that works wonderfully in mice, but less well in people. The issue seems to be that in people the lactone ring opens rapidly. I was never quite able to figure out if SUPG had licensed the patent extracted below that claims to solve this problem.
Here's the animal work:
ANTI-TUMOR EFFECTS OF RFS 2000 (9-NITRO-20(S)-CAMPTOTHECIN-9NC). B.C.
Giovanella, Z. Cao, D. Vardeman, J. Mendoza, T. Kozielski, C. Verschraegen,
J.S. Stehlin, Jr., The Stehlin Foundation for Cancer Research at St. Joseph
Hospital, Houston, TX.
A series of clinical trials* are now in progress with RFS 2000 (9NC). Very
promising results have been observed in Phase II trials, especially in
pancreatic carcinoma. Extensive in vivo preclinical studies demonstrated
impressive antitumor activity in a variety of tumors. Thirty-one human
tumors (10 Pancreas Ca, 5 Colon Ca, 4 Breast Ca, 4 Lung Ca, 2 Ovarian Ca, 2
Prostate Ca, 1 Stomach Ca, 2 Melanomas and 1 Leukemia) xenografted into nude
mice were treated with RFS 2000 (9NC) administered intrastomach,
intraperitoneally, intramuscularly and intravenously. The most effective
routes of administration were intramuscular (IM) (2 mg/kg, 2 × week × 4),
continuous infusion intraperitoneally (IP) (0.75 mg/kg/day 5 days on, 2 days
off × 4), and intrastomach (IS) (1.5 mg/kg/day, 5 days on, 2 days off × 4).
The least effective was intravenous (IV) bolus injection. All the tumors
responded (100% or more growth inhibition, frequently total tumor
disappearance) at maximum tolerated doses (MTD). When doses were reduced, it
was possible to differentiate between tumors responding only to the MTD and
others which responded to 1/2 or even to 1/4 of MTD. Work is in progress in
order to understand why some tumors are hypersensitive to RFS 2000 (9NC) and
to develop a clinical test to identify them before treatment. Artificial
liver metastases of colon carcinoma responded with a threefold increase in
survival (130+ days versus 42---some very long-term survivors). Mice were
given MTD for more than 200 days without ill effect. Toxicity, determined in
mice and dogs, was exclusively intestinal (inflammatory ileitis) and bone
marrow suppression. Both were fully reversible suspending treatment and
restarting at the same or at a lower dose. Supported by The Stehlin
Foundation and by The Friends of The Stehlin Foundation. *Sponsored by The
Stehlin Foundation and SuperGen, Inc.
And here's an interesting extract from the patent cited below:
"In perfect agreement with such findings, the clinical responses in this
group of patients, although higher than those obtained with CPT are still a
far cry below the results obtained in mice (32/32 complete tumor regressions
in mice versus 2/32 in humans). Clearly, again there is a pressing need for
a modification which will slow and delay the lactone ring opening upon its
entrance into the blood circulation. "
Here's the relevant patent:
United States Patent 5,731,316
Cao , et al. March 24, 1998
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Derivatives of camptothecin and methods of treating cancer using these
derivatives
Abstract
Derivatives of camptothecin are disclosed and are represented by the general
formula: ##STR1## wherein when R.sub.2 is H, R.sub.1 is a C.sub.2 -C.sub.15
alkyl group, a C.sub.2 -C.sub.15 alkenyl group or an epoxy group; and when
R.sub.2 is a nitro group, R.sub.1 is a C.sub.1 -C.sub.15 alkyl group, a
C.sub.1 -C.sub.15 alkenyl group or an epoxy group. Processes for making
these derivatives and for using them in cancer treatment are also disclosed.
<snip>
FIELD OF THE INVENTION
The present invention is directed to derivatives of camptothecin, preferably
having low toxicity, and to the use of these derivatives for cancer
treatment. The disclosures of all documents referred to in this application
are incorporated herein in whole by reference.
BACKGROUND OF THE INVENTION
Camptothecin, a cytotoxic alkaloid first isolated from the wood and bark of
Camptotheca Acuminata (Nyssaceae) by Wall and his coworkers (J. Am. Chem.
Soc. 88, 3888, 1966), was shown to have antitumor activity against the mouse
leukemia L 1210 system. The structure of camptothecin, an alkaloid which has
a commonly occurring indole alkaloid group (Heckendorf et al, J Org. Chem.
41, 2045, 1976), is shown below as Formula (X). ##STR2## This compound has a
pentacyclic ring system with only one asymmetrical center in ring E with a
20(S)-configuration. The pentacyclic ting system includes a pyrrolo ›3, 4 -
b!quinoline moiety (rings A, B and C), a conjugated pyridone (ring D), and a
six-membered lactone (ring E) with an .alpha.- hydroxyl group. Camptothecin
was of great interest from the time of its initial isolation due to its
noteworthy activity in the mouse leukemia L 1210 system. Earlier data for
the antitumor activity of camptothecin were obtained by employing
experimentally transplanted malignancies such as leukemia L 1210 in mice, or
Walker 256 tumor in rats (Chem. Rev. 23, 385, 1973, Cancer Treat. Rep. 60,
1007, 1967). Subsequent clinical studies showed that this compound was not
usable as an anticancer agent in vivo due to its high toxicity. Camptothecin
itself is insoluble in water. Therefore, camptothecin was evaluated
clinically as a water-soluble sodium carboxylate salt in the early times.
This form of camptothecin produced severe toxicity and seemed devoid of
anticancer activity (Gottlieb et al, Cancer Chemother. Rep. 54, 461, 1970,
and 56, 103, 1972, Muggia et al, Cancer Chemother. Rep. 56, 515, 1972,
Moertel et al, Cancer Chemother. Rep. 56, 95, 1972, and Schaeppi et al,
Cancer Chemother. Rep. 5:25, 1974). These results caused the discontinuation
of phase II trials. Continued evaluation of this agent showed that the
sodium carboxylate salt is only 10% as potent as the native camptothecin
with the closed lactone ring intact (Wall et al, In International Symposium
on Biochemistry And Physiology of The Alkaloids, Mothes et al, eds,
Academic--Verlag, Berlin, 77, 1969, Giovanella et al, Cancer res. 51, 3052,
1991). In addition, important parameters for antitumor activity in the
camptothecin family have been established (Wall et al, Ann. Rev., Pharmacol.
Toxicol. 17, 117, 1977). These results indicate that intact lactone ring E
and .alpha.-hydroxyl group are essential for antitumor activity.
In 1989, Giovanella et al. found that some of the non-water soluble
derivatives of camptothecin have high antitumor activity against xenograft
of human tumors (Giovanella et al., Science, 246, 1046, 1989). It has also
been shown that administration of camptothecin with closed lactone ring is
superior to injections of water-soluble carboxylate salt (Giovanella et al,
Cancer Res., 51, 3052, 1991). These findings further confirmed the
importance of the intact lactone ring.
Clearly, there is a need to modify 20(S)-camptothecin ("CPT") to enable the
lactone form to stay longer in the body while retaining the structural
elements (i.e. 20-hydroxyl and lactone ring E) which are essential for its
antitumor activity.
Ring opening of CPT leads to much more potent anticancer activity in mice
than in humans. In effect, CPT administered intramuscularly ("i.m."),
subcutaneously ("s.c."), and intrastomach ("i.s.") has proved to be a very
potent anticancer agent against human tumors in mice, i.e. , when growing as
xenotransplants in nude mice (Giovanella et al, Cancer Res. 51:3052, 1991).
However, when tumors were treated with CPT in humans, a lower degree of
anticancer activity in humans, than in mice, was exhibited (Stehlin et al.,
In Camptothecins: New Anticancer Agents, 1995, CRC Press, pp. 59-65).
The same phenomenon was observed with other CPT derivatives. In mice,
9-nitrocamptothecin ("9NC") has proven to be 2-3 times more potent than CPT
against human tumor xenografts causing the total eradication of all the
human malignancies treated (Pantazis et al., Cancer Res. 53:1577, 1993;
Pantazis et al., Int. J. Cancer 53:863, 1995).
Pharmacological studies demonstrated that the majority (57%) of the 9NC drug
present in the plasma after i.s. administration is in the closed lactone
form (FIG. 3). Pharmacological studies on the plasma levels of 9NC after
oral administration to Phase I clinical trial patients demonstrate that, on
average, only.about.3% of the drug present is in the closed lactone form
(FIGS. 4 and 5).
In perfect agreement with such findings, the clinical responses in this
group of patients, although higher than those obtained with CPT are still a
far cry below the results obtained in mice (32/32 complete tumor regressions
in mice versus 2/32 in humans). Clearly, again there is a pressing need for
a modification which will slow and delay the lactone ring opening upon its
entrance into the blood circulation.
A number of attempts have made to provide more active derivatives of
camptothecin, but none of these compounds has been disclosed to be able to
delay the opening of the lactone ring E.
SUMMARY OF THE INVENTION
Accordingly, it is an object of the present invention to provide new CPT
derivatives which are effective antitumor agents, preferably useful for the
oral and intramuscular routes of drug administration.
It is another object of the present invention to provide new active CPT
derivatives which sustain the opening of the lactone ring E, which makes the
antitumor activity last longer than its mother analog, CPT.
It is still another object of the present invention to provide new CPT
derivatives which retain significant antitumor activity as does the mother
compound, CPT, and have much lower toxicity than its mother compound.
It is still another object of the present invention to provide new CPT
derivatives possessing good absorbability in the living body.
It is a further object of the present invention to provide new CPT
derivatives which retain the lactone ring E and the 20 - hydroxyl group
intact, which are important for antitumor activity.
It is still a further object of the present invention to provide a method
for preparing CPT derivatives.
Additional objects and advantages of the present invention will be set forth
in part in the description which follows, and in part will be apparent from
the description, or may be learned by practice of the present invention. The
objects and advantages of the present invention will be realized and
attained by means of the elements and combinations particularly pointed out
in the appended claims.
To achieve the objects and in accordance with the purpose of the present
invention, as embodied and broadly described herein, the present invention
relates to a compound of formula (I): ##STR3## wherein R.sub.2 is H or
NO.sub.2, and R.sub.1 is a C.sub.2 -C.sub.15 alkyl group, a
C.sub.2 -C.sub.15 alkenyl group or an epoxy group when. R.sub.2 is H; and
R.sub.1 is a C.sub.1 -C.sub.15 alkyl group, a C.sub.2 -C.sub.15 alkenyl
group or an epoxy group when R.sub.2 is NO.sub.2.
The invention also relates to a method for treating malignant tumors in a
mammal and comprises administering an effective amount of one or more of the
above compounds.
This is an interesting area - well worth following up on for any chemically literate folks (which definitely doesn't include me - all I know about lactone rings is that they are smaller than a breadbox. <g>)
Peter |
