and 9-nitrocamptothecin are the widely used water-soluble semisynthetic analogues
of CPT for treating cancers all over the world. (Deorukhkar et al. 2007; Ramawat
and Goyal 2009; Raveendran 2015). Presently, they represent a distinctive class of
clinically approved chemo-drugs of modern medicines (Lee 1999; Ramawat and
Goyal 2009). The anticancer mechanism of action of these chemo-drugs is through
causing cellular damages by apoptosis intermediated by the inhibition of Top-I
(Topoisomerase I) enzyme structure and activity (Wright et al. 2015; Sadre et al.
2016). Though many leads are presently in clinical trials against cancers, only
topotecan and irinotecan are permitted for clinical uses (Martino et al. 2016; Pu
et al. 2019).
This chapter summarizes the occurrence of CPT in natural resources, chemistry,
and its mode of action. Overall, this comprehensive review encourages research
interest among chemists and biologists to explore more on this novel compound.
9.2 Camptothecin Discovery and Its Chemistry
In 1955, to evaluate the anticancer compounds from nature, Cancer Chemotherapy
National Service Center (CCNSC) was created by the National Cancer Institute
(NCI). It was initially aimed to screen unknown chemical compounds for
chemotherapeutic uses. However, later in the year 1960, the screening program was
extended to include different natural resources, mainly plant species and their
potential anticancer compounds. In this collaborative work, many pharmaceutical
companies and research institutions, including The United States Department of
Agriculture (USDA) submitted numerous potential plant species and phytocompounds to be screened for their antitumor activities (Hartwell 1970; Perdue et al.
1970; Moore et al. 1970; Raveendran 2015). The NCI screening work was led by a
well-known organic chemist, named Jonathan Hartwell, and it also included data
from the documents of traditional medical practices of Egypt, Greece, China, and
Rome that employed a wide range of medicinal plant species and their preparations
against cancer cure. Different plants species extracted initially at Wisconsin Alumni
Research Foundation was directed to many other labs for evaluating their potential
of killing cancerous cells. Primarily, the anticancer effects of all samples were
evaluated in oral epidermoid carcinoma (KB) cell culture. Also, the samples were
screened using tumor xenograft mouse models, i.e., CA-755, an adenocarcinoma;
S-180, a sarcoma; and L1210, a lymphoid leukemia (Kessel 1971a,b; Raveendran
2015). From these results, the crude extracts showing active antitumor activities
were later subjected to different separation techniques to isolate the active compounds at different laboratories, including Research Triangle Institute (RTI), North
Carolina. More than 1000 plant compounds were isolated from different plant
species solvent extracts, and among them, only Camptotheca accuminata, a tree
species bark and stem extract disclosed noteworthy anticancer activity. Further
screening and isolation techniques have led to the identification of novel compound,
which was named as CPT in 1966, and the new sequestration of this anticancer
9 Camptothecin: Occurrence, Chemistry and Mode of Action
313
of CPT for treating cancers all over the world. (Deorukhkar et al. 2007; Ramawat
and Goyal 2009; Raveendran 2015). Presently, they represent a distinctive class of
clinically approved chemo-drugs of modern medicines (Lee 1999; Ramawat and
Goyal 2009). The anticancer mechanism of action of these chemo-drugs is through
causing cellular damages by apoptosis intermediated by the inhibition of Top-I
(Topoisomerase I) enzyme structure and activity (Wright et al. 2015; Sadre et al.
2016). Though many leads are presently in clinical trials against cancers, only
topotecan and irinotecan are permitted for clinical uses (Martino et al. 2016; Pu
et al. 2019).
This chapter summarizes the occurrence of CPT in natural resources, chemistry,
and its mode of action. Overall, this comprehensive review encourages research
interest among chemists and biologists to explore more on this novel compound.
9.2 Camptothecin Discovery and Its Chemistry
In 1955, to evaluate the anticancer compounds from nature, Cancer Chemotherapy
National Service Center (CCNSC) was created by the National Cancer Institute
(NCI). It was initially aimed to screen unknown chemical compounds for
chemotherapeutic uses. However, later in the year 1960, the screening program was
extended to include different natural resources, mainly plant species and their
potential anticancer compounds. In this collaborative work, many pharmaceutical
companies and research institutions, including The United States Department of
Agriculture (USDA) submitted numerous potential plant species and phytocompounds to be screened for their antitumor activities (Hartwell 1970; Perdue et al.
1970; Moore et al. 1970; Raveendran 2015). The NCI screening work was led by a
well-known organic chemist, named Jonathan Hartwell, and it also included data
from the documents of traditional medical practices of Egypt, Greece, China, and
Rome that employed a wide range of medicinal plant species and their preparations
against cancer cure. Different plants species extracted initially at Wisconsin Alumni
Research Foundation was directed to many other labs for evaluating their potential
of killing cancerous cells. Primarily, the anticancer effects of all samples were
evaluated in oral epidermoid carcinoma (KB) cell culture. Also, the samples were
screened using tumor xenograft mouse models, i.e., CA-755, an adenocarcinoma;
S-180, a sarcoma; and L1210, a lymphoid leukemia (Kessel 1971a,b; Raveendran
2015). From these results, the crude extracts showing active antitumor activities
were later subjected to different separation techniques to isolate the active compounds at different laboratories, including Research Triangle Institute (RTI), North
Carolina. More than 1000 plant compounds were isolated from different plant
species solvent extracts, and among them, only Camptotheca accuminata, a tree
species bark and stem extract disclosed noteworthy anticancer activity. Further
screening and isolation techniques have led to the identification of novel compound,
which was named as CPT in 1966, and the new sequestration of this anticancer
9 Camptothecin: Occurrence, Chemistry and Mode of Action
313