The Rosy Periwinkle Catharanthus roseus How Catharanthus Alkaloids are used to treat diseases. Bethany Highsmith

Call me Pinkie!  Formerly classified Formerly classified as Vinca rosea, has also been classified as: Lochnera rosea & Ammocallis rosea  Common Names:  Madagascar Periwinkle  Cape Periwinkle  Old Maid  Cultivars in the 1960s: Cultivars in the 1960s:  Little Blanche  Little Bright Eye  Little Delicata  Little Pinkie  Known as “Kanniedood” in the South African vernacular (cannot die)  French referred to it as the “violet of the sorcerers”  Formerly classified Formerly classified as Vinca rosea, has also been classified as: Lochnera rosea & Ammocallis rosea  Common Names:  Madagascar Periwinkle  Cape Periwinkle  Old Maid  Cultivars in the 1960s: Cultivars in the 1960s:  Little Blanche  Little Bright Eye  Little Delicata  Little Pinkie  Known as “Kanniedood” in the South African vernacular (cannot die)  French referred to it as the “violet of the sorcerers”

What are Catharanthus Alkaloids?  Alkaloids: Bitter tasting, nitrogenous compounds that are alkaline in their chemical properties.  Catharanthus alkaloids are “the most important plant source of materials used in chemotherapy.”  Although there are approximately 130 alkaloids in Catharanthus roseus, there are four major ones in clinical use:  Vinblastine  Vincristine  Vindesine  Vinorelbine  Alkaloids: Bitter tasting, nitrogenous compounds that are alkaline in their chemical properties.  Catharanthus alkaloids are “the most important plant source of materials used in chemotherapy.”  Although there are approximately 130 alkaloids in Catharanthus roseus, there are four major ones in clinical use:  Vinblastine  Vincristine  Vindesine  Vinorelbine

How are the Catharanthus alkaloids used to treat diseases?  Administered intravenously  Metabolized by the liver & excreted  Work by stopping mitosis of affected cells, thus causing cell death  Bind to the tubulin monomers & prevent microtubules from forming so that the chromosomes can ’ t separate (mitosis stops in metaphase)  Administered intravenously  Metabolized by the liver & excreted  Work by stopping mitosis of affected cells, thus causing cell death  Bind to the tubulin monomers & prevent microtubules from forming so that the chromosomes can ’ t separate (mitosis stops in metaphase)

The History of Catharanthus roseus  The pantropical distribution of C. roseus was caused by sailors  Brazilian remedy for hemorrhoids and scabies.  Periwinkle was originally studied in the lab as a cure for diabetes, not for cancer.  Jamaican Periwinkle tea  Supply of leaves was insufficient for research  Catharanthus roseus was grown in Canada.  Finally, vinblastine was isolated in 1957 in Dr. J.B. Collip ’ s Department of Medical Research at the University of Western Ontario.  The pantropical distribution of C. roseus was caused by sailors  Brazilian remedy for hemorrhoids and scabies.  Periwinkle was originally studied in the lab as a cure for diabetes, not for cancer.  Jamaican Periwinkle tea  Supply of leaves was insufficient for research  Catharanthus roseus was grown in Canada.  Finally, vinblastine was isolated in 1957 in Dr. J.B. Collip ’ s Department of Medical Research at the University of Western Ontario.

Vinblastine: Its Description  Introduced in 1960  Used to treat: Hodgkin’s disease, non- Hodgkin lymphomas, testisicular cancer, breast cancer, and choriocarcinoma  Introduced in 1960  Used to treat: Hodgkin’s disease, non- Hodgkin lymphomas, testisicular cancer, breast cancer, and choriocarcinoma

Vinblastine: Chemical Structure

Vincristine: Described  Introduced in 1963  Used to treat: acute leukemia, Hodgkin’s disease, non-Hodgkin lymphomas, rhabdomyosarcomas, Wilm’s tumors in children, and breast cancer  Introduced in 1963  Used to treat: acute leukemia, Hodgkin’s disease, non-Hodgkin lymphomas, rhabdomyosarcomas, Wilm’s tumors in children, and breast cancer

Vincristine: Chemical Structure

Vindesine: Described  Introduced in 1980  Used to treat: leukemias, bronchus cancer, breast cancer, myeloma, and colorectal cancer  Introduced in 1980  Used to treat: leukemias, bronchus cancer, breast cancer, myeloma, and colorectal cancer

Vindesine: Chemical Structure

Vinorelbine  Introduced in 1995  Used to treat: non-small cell lung cancer, testicular cancer, epithelial ovarian cancer, and breast cancer  Introduced in 1995  Used to treat: non-small cell lung cancer, testicular cancer, epithelial ovarian cancer, and breast cancer

How are Catharanthus Alkaloids cultivated?  Major areas for cultivation:  Southern USA  Mexico  South America  Middle East  China  India  Semi-synthetic Synthesis from Catharanthine and Vindoline  Producing Vincristine from Vinblastine  Major areas for cultivation:  Southern USA  Mexico  South America  Middle East  China  India  Semi-synthetic Synthesis from Catharanthine and Vindoline  Producing Vincristine from Vinblastine

Experiments that have been done for treatment  In Humans  1960s study by Marmont & Damasio  Dutch study on the Pharmokinetics of Vincristine Monotherapy in Childhood Acute Lymphoblastic Leukemia  In Mice  The Effect of Vinca Alkaloids on Tumor Blood Flow  In Humans  1960s study by Marmont & Damasio  Dutch study on the Pharmokinetics of Vincristine Monotherapy in Childhood Acute Lymphoblastic Leukemia  In Mice  The Effect of Vinca Alkaloids on Tumor Blood Flow

A Quick Summary of Medicines & Diseases  Vinblastine  Velban  Velbe  Vincristine  Oncovin  Vindesine  Fildesin  Eldisine  Vinorelbine  Navelbine  Vinblastine  Velban  Velbe  Vincristine  Oncovin  Vindesine  Fildesin  Eldisine  Vinorelbine  Navelbine  Breast cancer  Lung cancer  Acute lymphoblastic leukemia  Hodgkin’s disease  Non-Hodgkin’s lymphomas  Others

 DO NOT try eating or smoking rosy periwinkle for “medicinal purposes.”  Periwinkle is POISONOUS if smoked or ingested  Horrible side effects!  Birth defects  Neurotoxicity, peripheral neuropathy  Loss ofpetite  Loss of appetite, nausea, cramps & constipation  Fever  Amenorrhoea  Hair loss  Incontinence  Mouth ulcers, jaw pain  Increased risk of infections  Nosebleeds, bleeding gums, bruises  Pain and discoloration along vein  DO NOT try eating or smoking rosy periwinkle for “medicinal purposes.”  Periwinkle is POISONOUS if smoked or ingested  Horrible side effects!  Birth defects  Neurotoxicity, peripheral neuropathy  Loss ofpetite  Loss of appetite, nausea, cramps & constipation  Fever  Amenorrhoea  Hair loss  Incontinence  Mouth ulcers, jaw pain  Increased risk of infections  Nosebleeds, bleeding gums, bruises  Pain and discoloration along vein A Final Word of Caution

Bibliography  “Catharanthus roseus-Drugs and Vitamins-Drug Library-Drug Digest”. June 2, Accesed April 19,  Damasio, Eugenio E. and Alberto M. Marmont. “The Effects of Two Alkaloids Derived from Vinca rosea on the Malignant Cells of Hodgkin’s Disease, Lymphosarcoma and Acute Leukemia in Vivo.” Blood, Vol. 29, No. 1 (January), pp  “Description and Natural History of the Periwinkle”.. November 5, Accessed April 15,  Groninger, Ellis, et.al. “Pharmacokinetics of Vincristine Monotherapy in Childhood Acute Lymphoblastic Leukemia.”  Hill, S.A., et.al. “The Effect of Vinca Alkaloids on Tumour Blood Flow”. Advances in Experimental Medicine and Biology Pp  Noble, Robert L. “The Discovery of the Vinca Alkaloids-Chemotherapeutic Agents against Cancer.” Biochemistry and Cell Biology. Vol. 68. Pp  Van der Heijden,Robert, et.al. “The Catharanthus Alkaloids: Pharmacognasy and Biotechnology.” Current Medicinal Chemistry, 2004, Vol.11, p  “Vindesine”. CancerQuest. Emory University.. June 25, Accessed April 28,  “Vinorelbine (Navelbine)”.. December 30, Accessed April 26,  “Catharanthus roseus-Drugs and Vitamins-Drug Library-Drug Digest”. June 2, Accesed April 19,  Damasio, Eugenio E. and Alberto M. Marmont. “The Effects of Two Alkaloids Derived from Vinca rosea on the Malignant Cells of Hodgkin’s Disease, Lymphosarcoma and Acute Leukemia in Vivo.” Blood, Vol. 29, No. 1 (January), pp  “Description and Natural History of the Periwinkle”.. November 5, Accessed April 15,  Groninger, Ellis, et.al. “Pharmacokinetics of Vincristine Monotherapy in Childhood Acute Lymphoblastic Leukemia.”  Hill, S.A., et.al. “The Effect of Vinca Alkaloids on Tumour Blood Flow”. Advances in Experimental Medicine and Biology Pp  Noble, Robert L. “The Discovery of the Vinca Alkaloids-Chemotherapeutic Agents against Cancer.” Biochemistry and Cell Biology. Vol. 68. Pp  Van der Heijden,Robert, et.al. “The Catharanthus Alkaloids: Pharmacognasy and Biotechnology.” Current Medicinal Chemistry, 2004, Vol.11, p  “Vindesine”. CancerQuest. Emory University.. June 25, Accessed April 28,  “Vinorelbine (Navelbine)”.. December 30, Accessed April 26, 2006.